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1. Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

Author

Vincent Jonchère, Hugo Montémont, Enora Le Scanf, Aurélie Siret, Quentin Letourneur, Emmanuel Tubacher, Christophe Battail, Assane Fall, Karim Labreche, Victor Renault, Toky Ratovomanana, Olivier Buhard, Ariane Jolly, Philippe Le Rouzic, Cody Feys, Emmanuelle Despras, Habib Zouali, Rémy Nicolle, Pascale Cervera, Magali Svrcek, Pierre Bourgoin, Hélène Blanché, Anne Boland, Jérémie Lefèvre, Yann Parc, Mehdi Touat, Franck Bielle, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos, Gaël Quéré, Gwendal Dujardin, Marc Blondel, Cédric Le Maréchal, Romain Cohen, Thierry André, Florence Coulet, Pierre de la Grange, Aurélien de Reyniès, Jean-François Fléjou, Florence Renaud, Agusti Alentorn, Laurent Corcos, Jean-François Deleuze, Ada Collura, and Alex Duval

Subjects
Colorectal cancer, Mismatch repair deficiency, Microsatellite instability, Whole-exome and RNA sequencing, Alternative splicing, Polypyrimidine U2AF binding site, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. Results Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. Conclusions Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

Published
2024
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2. Large-scale phosphoproteomics reveals activation of the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells

Author

Mohammad Al Tarrass, Lucid Belmudes, Dzenis Koça, Valentin Azemard, Hequn Liu, Tala Al Tabosh, Delphine Ciais, Agnès Desroches-Castan, Christophe Battail, Yohann Couté, Claire Bouvard, and Sabine Bailly

Subjects
BMP9, BMP10, Endothelial cells, Signaling, Phosphoproteomics, MAPK, Medicine, Cytology, QH573-671
Abstract

Abstract Background BMP9 and BMP10 are two major regulators of vascular homeostasis. These two ligands bind with high affinity to the endothelial type I kinase receptor ALK1, together with a type II receptor, leading to the direct phosphorylation of the SMAD transcription factors. Apart from this canonical pathway, little is known. Interestingly, mutations in this signaling pathway have been identified in two rare cardiovascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. Methods To get an overview of the signaling pathways modulated by BMP9 and BMP10 stimulation in endothelial cells, we employed an unbiased phosphoproteomic-based strategy. Identified phosphosites were validated by western blot analysis and regulated targets by RT-qPCR. Cell cycle analysis was analyzed by flow cytometry. Results Large-scale phosphoproteomics revealed that BMP9 and BMP10 treatment induced a very similar phosphoproteomic profile. These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway and demonstrated that this activation required the expression of the protein GADD45β. In turn, activated P38 phosphorylated the heat shock protein HSP27 and the endocytosis protein Eps15 (EGF receptor pathway substrate), and regulated the expression of specific genes (E-selectin, hyaluronan synthase 2 and cyclooxygenase 2). This study also highlighted the modulation in phosphorylation of proteins involved in transcriptional regulation (phosphorylation of the endothelial transcription factor ERG) and cell cycle inhibition (CDK4/6 pathway). Accordingly, we found that BMP10 induced a G1 cell cycle arrest and inhibited the mRNA expression of E2F2, cyclinD1 and cyclinA1. Conclusions Overall, our phosphoproteomic screen identified numerous proteins whose phosphorylation state is impacted by BMP9 and BMP10 treatment, paving the way for a better understanding of the molecular mechanisms regulated by BMP signaling in vascular diseases.

Published
2024
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3. A microfluidic platform integrating functional vascularized organoids-on-chip

Author

Clément Quintard, Emily Tubbs, Gustav Jonsson, Jie Jiao, Jun Wang, Nicolas Werschler, Camille Laporte, Amandine Pitaval, Thierno-Sidy Bah, Gideon Pomeranz, Caroline Bissardon, Joris Kaal, Alexandra Leopoldi, David A. Long, Pierre Blandin, Jean-Luc Achard, Christophe Battail, Astrid Hagelkruys, Fabrice Navarro, Yves Fouillet, Josef M. Penninger, and Xavier Gidrol

Subjects
Science
Abstract

Abstract The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.

Published
2024
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4. A new scaffold-free tumoroid model provides a robust preclinical tool to investigate invasion and drug response in Renal Cell Carcinoma

Author

Irinka Séraudie, Catherine Pillet, Beatrice Cesana, Pauline Bazelle, Florian Jeanneret, Bertrand Evrard, Frédéric Chalmel, Assilah Bouzit, Christophe Battail, Jean-Alexandre Long, Jean Luc Descotes, Claude Cochet, and Odile Filhol

Subjects
Cytology, QH573-671
Abstract

Abstract Clear cell Renal Cell Carcinoma (ccRCC) is one of the most prevalent kidney cancers, which is often asymptomatic and thus discovered at a metastatic state (mRCC). mRCC are highly heterogeneous tumors composed of subclonal populations that lead to poor treatment response rate. Several recent works explored the potential of ccRCC tumoroids culture derived from patients. However, these models were produced following a scaffold-based method using collagen I or Matrigel that exhibit lot variability and whose complexity could induce treatment response modifications and phenotypic alterations. Following the observation that ccRCC tumoroids can create their own niche by secreting extracellular matrix components, we developed the first scaffold-free tumoroid model of ccRCC tumors. Tumoroids from mice as well as from human tumors were generated with high success rate (≥90%) using a magnetic suspension method and standard culture media. Immunofluorescence analysis revealed their self-organization capacities to maintain multiple tumor-resident cell types, including endothelial progenitor cells. Transcriptomic analysis showed the reproducibility of the method highlighting that the majority of gene expression patterns was conserved in tumoroids compared to their matching tumor tissue. Moreover, this model enables to evaluate drug effects and invasiveness of renal cancer cells in a 3D context, providing a robust preclinical tool for drug screening and biomarker assessment in line with alternative ex vivo methods like tumor tissue slice culture or in vivo xenograft models.

Published
2023
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5. Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric αD pocket

Author

Alexandre Bancet, Rita Frem, Florian Jeanneret, Angélique Mularoni, Pauline Bazelle, Caroline Roelants, Jean-Guy Delcros, Jean-François Guichou, Catherine Pillet, Isabelle Coste, Toufic Renno, Christophe Battail, Claude Cochet, Thierry Lomberget, Odile Filhol, and Isabelle Krimm

Subjects
Molecular biology, Cell biology, Structural biology, Cancer, Science
Abstract

Summary: Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further exploring its therapeutic potential. Here, we report the discovery of AB668, an outstanding selective inhibitor that binds CK2 through a bivalent mode, interacting both at the ATP site and an allosteric αD pocket unique to CK2. Using caspase activation assay, live-cell imaging, and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to representative ATP-competitive inhibitors, CX-4945, and SGC-CK2-1. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 αD pocket, has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death in several cancer cell lines and stimulating distinct biological pathways in renal cell carcinoma.

Published
2024
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6. CK2β Is a Gatekeeper of Focal Adhesions Regulating Cell Spreading

Author

Odile Filhol, Anne-Marie Hesse, Anne-Pascale Bouin, Corinne Albigès-Rizo, Florian Jeanneret, Christophe Battail, Delphine Pflieger, and Claude Cochet

Subjects
CK2β depletion, EMT, tyrosine-phosphorylated proteins, FAK1-Src-PAX1 signaling pathway, focal adhesions, epithelial cell spreading, Biology (General), QH301-705.5
Abstract

CK2 is a hetero-tetrameric serine/threonine protein kinase made up of two CK2α/αʹ catalytic subunits and two CK2β regulatory subunits. The free CK2α subunit and the tetrameric holoenzyme have distinct substrate specificity profiles, suggesting that the spatiotemporal organization of the individual CK2 subunits observed in living cells is crucial in the control of the many cellular processes that are governed by this pleiotropic kinase. Indeed, previous studies reported that the unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition (EMT), a process involved in cancer invasion and metastasis. Moreover, sub-stoichiometric expression of CK2β compared to CK2α in a subset of breast cancer tumors was correlated with the induction of EMT markers and increased epithelial cell plasticity in breast carcinoma progression. Phenotypic changes of epithelial cells are often associated with the activation of phosphotyrosine signaling. Herein, using phosphotyrosine enrichment coupled with affinity capture and proteomic analysis, we show that decreased expression of CK2β in MCF10A mammary epithelial cells triggers the phosphorylation of a number of proteins on tyrosine residues and promotes the striking activation of the FAK1-Src-PAX1 signaling pathway. Moreover, morphometric analyses also reveal that CK2β loss increases the number and the spatial distribution of focal adhesion signaling complexes that coordinate the adhesive and migratory processes. Together, our findings allow positioning CK2β as a gatekeeper for cell spreading by restraining focal adhesion formation and invasion of mammary epithelial cells.

Published
2022
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7. Region-specific expression of young small-scale duplications in the human central nervous system

Author

Solène Brohard-Julien, Vincent Frouin, Vincent Meyer, Smahane Chalabi, Jean-François Deleuze, Edith Le Floch, and Christophe Battail

Subjects
Paralog, Small scale duplication, Brain region-specific expression, Human central nervous system, Gene co-expression network, Ecology, QH540-549.5, Evolution, QH359-425
Abstract

Abstract Background The duplication of genes is one of the main genetic mechanisms that led to the gain in complexity of biological tissue. Although the implication of duplicated gene expression in brain evolution was extensively studied through comparisons between organs, their role in the regional specialization of the adult human central nervous system has not yet been well described. Results Our work explored intra-organ expression properties of paralogs through multiple territories of the human central nervous system (CNS) using transcriptome data generated by the Genotype-Tissue Expression (GTEx) consortium. Interestingly, we found that paralogs were associated with region-specific expression in CNS, suggesting their involvement in the differentiation of these territories. Beside the influence of gene expression level on region-specificity, we observed the contribution of both duplication age and duplication type to the CNS region-specificity of paralogs. Indeed, we found that small scale duplicated genes (SSDs) and in particular ySSDs (SSDs younger than the 2 rounds of whole genome duplications) were more CNS region-specific than other paralogs. Next, by studying the two paralogs of ySSD pairs, we observed that when they were region-specific, they tend to be specific to the same region more often than for other paralogs, showing the high co-expression of ySSD pairs. The extension of this analysis to families of paralogs showed that the families with co-expressed gene members (i.e. homogeneous families) were enriched in ySSDs. Furthermore, these homogeneous families tended to be region-specific families, where the majority of their gene members were specifically expressed in the same region. Conclusions Overall, our study suggests the involvement of ySSDs in the differentiation of human central nervous system territories. Therefore, we show the relevance of exploring region-specific expression of paralogs at the intra-organ level.

Published
2021
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8. Co-Transplantation of Barcoded Lymphoid-Primed Multipotent (LMPP) and Common Lymphocyte (CLP) Progenitors Reveals a Major Contribution of LMPP to the Lymphoid Lineage

Author

Victoria Michaels, Smahane Chalabi, Agnes Legrand, Julie Renard, Emmanuel Tejerina, Marina Daouya, Sylvie Fabrega, Jérôme Megret, Robert Olaso, Anne Boland, Jean-François Deleuze, Christophe Battail, Diana Tronik-Le Roux, and Sophie Ezine

Subjects
lymphoid progenitors, cell labeling, genome barcoding, thymus, bone marrow graft, lentivirus, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a valuable option to restore proper immune function. However, delayed T cell reconstitution is observed compared to other lineages. To overcome this difficulty, we developed a new approach to identify populations with efficient lymphoid reconstitution properties. To this end, we use a DNA barcoding strategy based on the insertion into a cell chromosome of a lentivirus (LV) carrying a non-coding DNA fragment named barcode (BC). These will segregate through cell divisions and be present in cells’ progeny. The remarkable characteristic of the method is that different cell types can be tracked simultaneously in the same mouse. Thus, we in vivo barcoded LMPP and CLP progenitors to test their ability to reconstitute the lymphoid lineage. Barcoded progenitors were co-grafted in immuno-compromised mice and their fate analyzed by evaluating the BC composition in transplanted mice. The results highlight the predominant role of LMPP progenitors for lymphoid generation and reveal valuable novel insights to be reconsidered in clinical transplantation assays.

Published
2023
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9. Temporal Gene Expression Profiles Reflect the Dynamics of Lymphoid Differentiation

Author

Smahane Chalabi, Agnes Legrand, Victoria Michaels, Marie-Ange Palomares, Robert Olaso, Anne Boland, Jean-François Deleuze, Sophie Ezine, Christophe Battail, and Diana Tronik-Le Roux

Subjects
lymphopoiesis, hematopoietic differentiation, RNAseq, long non-coding RNA, transcriptome, gene networks, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Understanding the emergence of lymphoid committed cells from multipotent progenitors (MPP) is a great challenge in hematopoiesis. To gain deeper insight into the dynamic expression changes associated with these transitions, we report the quantitative transcriptome of two MPP subsets and the common lymphoid progenitor (CLP). While the transcriptome is rather stable between MPP2 and MPP3, expression changes increase with differentiation. Among those, we found that pioneer lymphoid genes such as Rag1, Mpeg1, and Dntt are expressed continuously from MPP2. Others, such as CD93, are CLP specific, suggesting their potential use as new markers to improve purification of lymphoid populations. Notably, a six-transcription factor network orchestrates the lymphoid differentiation program. Additionally, we pinpointed 24 long intergenic-non-coding RNA (lincRNA) differentially expressed through commitment and further identified seven novel forms. Collectively, our approach provides a comprehensive landscape of coding and non-coding transcriptomes expressed during lymphoid commitment.

Published
2022
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10. Gene flow contributes to diversification of the major fungal pathogen Candida albicans

Author

Jeanne Ropars, Corinne Maufrais, Dorothée Diogo, Marina Marcet-Houben, Aurélie Perin, Natacha Sertour, Kevin Mosca, Emmanuelle Permal, Guillaume Laval, Christiane Bouchier, Laurence Ma, Katja Schwartz, Kerstin Voelz, Robin C. May, Julie Poulain, Christophe Battail, Patrick Wincker, Andrew M. Borman, Anuradha Chowdhary, Shangrong Fan, Soo Hyun Kim, Patrice Le Pape, Orazio Romeo, Jong Hee Shin, Toni Gabaldon, Gavin Sherlock, Marie-Elisabeth Bougnoux, and Christophe d’Enfert

Subjects
Science
Abstract

The fungal pathogen Candida albicans can undergo a parasexual process that may contribute to genetic diversity, but its actual relevance is unclear. Here, Ropars et al. analyse the genomic sequences of 182 C. albicans isolates collected worldwide and find evidence of gene flow and thus parasexuality in nature.

Published
2018
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11. Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

Author

Constance Collet, Jonathan Lopez, Christophe Battail, Fabienne Allias, Mojgan Devouassoux-Shisheboran, Sophie Patrier, Nicolas Lemaitre, Touria Hajri, Jérôme Massardier, Benoit You, François Mallet, François Golfier, Nadia Alfaidy, and Pierre-Adrien Bolze

Subjects
gestational trophoblastic disease, gestational trophoblastic neoplasia, choriocarcinoma, hydatidiform mole, trophoblast, placenta, Biology (General), QH301-705.5
Abstract

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets.

Published
2021
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12. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

Author

Ludovic Arandel, Micaela Polay Espinoza, Magdalena Matloka, Audrey Bazinet, Damily De Dea Diniz, Naïra Naouar, Frédérique Rau, Arnaud Jollet, Frédérique Edom-Vovard, Kamel Mamchaoui, Mark Tarnopolsky, Jack Puymirat, Christophe Battail, Anne Boland, Jean-Francois Deleuze, Vincent Mouly, Arnaud F. Klein, and Denis Furling

Subjects
Myotonic dystrophy, Expanded repeats, Muscle cell line, Nuclear aggregates, Alternative splicing, Therapeutic compounds, Medicine, Pathology, RB1-214
Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.

Published
2017
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13. Bdf1 Bromodomains Are Essential for Meiosis and the Expression of Meiotic-Specific Genes.

Author

Encar García-Oliver, Claire Ramus, Jonathan Perot, Marie Arlotto, Morgane Champleboux, Flore Mietton, Christophe Battail, Anne Boland, Jean-François Deleuze, Myriam Ferro, Yohann Couté, and Jérôme Govin

Subjects
Genetics, QH426-470
Abstract

Bromodomain and Extra-terminal motif (BET) proteins play a central role in transcription regulation and chromatin signalling pathways. They are present in unicellular eukaryotes and in this study, the role of the BET protein Bdf1 has been explored in Saccharomyces cerevisiae. Mutation of Bdf1 bromodomains revealed defects on both the formation of spores and the meiotic progression, blocking cells at the exit from prophase, before the first meiotic division. This phenotype is associated with a massive deregulation of the transcription of meiotic genes and Bdf1 bromodomains are required for appropriate expression of the key meiotic transcription factor NDT80 and almost all the Ndt80-inducible genes, including APC complex components. Bdf1 notably accumulates on the promoter of Ndt80 and its recruitment is dependent on Bdf1 bromodomains. In addition, the ectopic expression of NDT80 during meiosis partially bypasses this dependency. Finally, purification of Bdf1 partners identified two independent complexes with Bdf2 or the SWR complex, neither of which was required to complete sporulation. Taken together, our results unveil a new role for Bdf1 -working independently from its predominant protein partners Bdf2 and the SWR1 complex-as a regulator of meiosis-specific genes.

Published
2017
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14. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin

Author

Delphine Laustriat, Jacqueline Gide, Laetitia Barrault, Emilie Chautard, Clara Benoit, Didier Auboeuf, Anne Boland, Christophe Battail, François Artiguenave, Jean-François Deleuze, Paule Bénit, Pierre Rustin, Sylvia Franc, Guillaume Charpentier, Denis Furling, Guillaume Bassez, Xavier Nissan, Cécile Martinat, Marc Peschanski, and Sandrine Baghdoyan

Subjects
alternative splicing, AMPK, Metformin, myotonic dystrophy type 1, RBM3, Therapeutics. Pharmacology, RM1-950
Abstract

Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.

Published
2015
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15. The spatiotemporal program of DNA replication is associated with specific combinations of chromatin marks in human cells.

Author

Franck Picard, Jean-Charles Cadoret, Benjamin Audit, Alain Arneodo, Adriana Alberti, Christophe Battail, Laurent Duret, and Marie-Noelle Prioleau

Subjects
Genetics, QH426-470
Abstract

The duplication of mammalian genomes is under the control of a spatiotemporal program that orchestrates the positioning and the timing of firing of replication origins. The molecular mechanisms coordinating the activation of about [Formula: see text] predicted origins remain poorly understood, partly due to the intrinsic rarity of replication bubbles, making it difficult to purify short nascent strands (SNS). The precise identification of origins based on the high-throughput sequencing of SNS constitutes a new methodological challenge. We propose a new statistical method with a controlled resolution, adapted to the detection of replication origins from SNS data. We detected an average of 80,000 replication origins in different cell lines. To evaluate the consistency between different protocols, we compared SNS detections with bubble trapping detections. This comparison demonstrated a good agreement between genome-wide methods, with 65% of SNS-detected origins validated by bubble trapping, and 44% of bubble trapping origins validated by SNS origins, when compared at the same resolution. We investigated the interplay between the spatial and the temporal programs of replication at fine scales. We show that most of the origins detected in regions replicated in early S phase are shared by all the cell lines investigated whereas cell-type-specific origins tend to be replicated in late S phase. We shed a new light on the key role of CpG islands, by showing that 80% of the origins associated with CGIs are constitutive. Our results further show that at least 76% of CGIs are origins of replication. The analysis of associations with chromatin marks at different timing of cell division revealed new potential epigenetic regulators driving the spatiotemporal activity of replication origins. We highlight the potential role of H4K20me1 and H3K27me3, the coupling of which is correlated with increased efficiency of replication origins, clearly identifying those marks as potential key regulators of replication origins.

Published
2014
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16. The immunopeptidome from a genomic perspective:Establishing the noncanonical landscape of MHC class I–associated peptides

Author

Georges Bedran, Hans-Christof Gasser, Kenneth Weke, Tongjie Wang, Dominika Bedran, Alexander Laird, Christophe Battail, Fabio Massimo Zanzotto, Catia Pesquita, Håkan Axelson, Ajitha Rajan, David J. Harrison, Aleksander Palkowski, Maciej Pawlik, Maciej Parys, J. Robert O'Neill, Paul M. Brennan, Stefan N. Symeonides, David R. Goodlett, Kevin Litchfield, Robin Fahraeus, Ted R. Hupp, Sachin Kote, Javier A. Alfaro, European Commission, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, and University of St Andrews. Cellular Medicine Division

Subjects
non-canonical MHC class I–associated peptides, Cancer Research, Tumour antigens, SDG 3 - Good Health and Well-being, tumor antigens, MCP, Immunology, DAS, shared antigens, Non-canonical MHC class I-associated peptides, Cancer, mass spectrometry
Abstract

G.B., D.B., K.W., A.P., R.F., T.R.H., S.K., and J.A.A. received support from Fundacja na rzecz Nauki Polskiej (FNP) (grant ID: MAB/3/2017). D.R.G. received support from Genome Canada & Genome BC (grant ID: 264PRO). D.J.H. received support from NuCana plc (grant ID: SMD0-ZIUN05). H.A. received support from Swedish Cancer Foundation (grant ID: 211709). H.G. received support from United Kingdom Research and Innovation (UKRI) (grant ID: EP/S02431X/1). C.P. received support from Fundação para a Ciência e a Tecnologia (FCT) through LASIGE Research Unit (grant ID: UIDB/00408/2020 and UIDP/00408/2020). A.L. F.M.Z., C.P., A.R., A.P., and J.A.A. received support from European Union’s Horizon 2020 research and innovation programme (grant ID: 101017453). C.B. received support from Agence Nationale de la Recherche (ANR) through GRAL LabEX (grant ID: ANR-10-LABX-49-01) and CBH-EUR-GS 32 (grant ID: ANR-17-EURE0003). S.N.S. received support from Cancer Research UK (CRUK) and the Chief Scientist's Office of Scotland (CSO): Experimental Cancer Medicine Centre (ECMC) (grant ID: ECMCQQR-2022/100017). A.L. received support from Chief Scientist's Office of Scotland (CSO) NRS Career Researcher Fellowship. R.O.N. received support from CRUK Cambridge Centre Thoracic Cancer Programme (grant ID: CTRQQR-2021\100012). Tumor antigens can emerge through multiple mechanisms, including translation of non-coding genomic regions. This non-canonical category of antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry to enable the discovery of non-canonical MHC-associated peptides (ncMAPs) from non-coding regions. Considering that the emergence of tumor antigens can also involve post-translational modifications, we included an open search component in our pipeline. Leveraging the wealth of mass spectrometry-based immunopeptidomics, we analyzed 26 MHC class I immunopeptidomic studies of 9 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant post-translational modifications, using spectral matching and controlled their false discovery rate (FDR) to 1%. Interestingly, the non-canonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 54.85%. Here, we reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targeting agents for T-cell therapies or vaccine development. Publisher PDF

Published
2023

17. A new scaffold-free tumoroid model provides a robust preclinical tool to investigate invasion and drug response in Renal Cell Carcinoma

Author

Odile Filhol, Irinka Séraudie, Catherine Pillet, Beatrice Cesana, Pauline Bazelle, Florian Jeanneret, Bertrand Evrard, Frederic Chalmel, Assilah Bouzit, Jean-Alexandre Long, Jean-Luc Descotes, Claude Cochet, and Christophe Battail

Abstract

Clear cell Renal Cell Carcinoma (ccRCC) is one of the most prevalent kidney cancers, which is often asymptomatic and thus discovered at a metastatic state (mRCC). mRCC are highly heterogeneous tumors composed of subclonal populations that lead to poor treatment response rate. Several recent works explored the potential of ccRCC tumoroids culture derived from patients. However, these models were produced following a scaffold-based method using collagen I or Matrigel that exhibit lot variability and whose complexity could induce treatment response modifications and phenotypic alterations. Following the observation that ccRCC tumoroids can create their own niche by secreting extracellular matrix components, we developed the first scaffold-free tumoroid model of ccRCC tumors. Tumoroids from mice as well as from human tumors were generated with high success rate (≥90 %) using a magnetic suspension method and standard culture media. Immunofluorescence analysis revealed their self-organization capacities to maintain multiple tumor-resident cell types, including endothelial progenitor cells. Transcriptomic analysis showed the reproducibility of the method highlighting that the majority of gene expression patternswas conserved in tumoroids compared to their matching tumor tissue. Moreover, this model enables to evaluate drug effects and invasiveness of renal cancer cells in a 3D context, providing a robust preclinical tool for drug screening and biomarker assessment in line with alternative ex vivo methods like tumor tissue slice culture or in vivoxenograft models.

Published
2023

18. Supplementary Table 3 from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Annotation of the COD-dipp ncMAPs.

Published
2023

19. Supplementary Table 2 from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Open search peptide-spectrum matches (PSMs) information of serine acetylation, cysteinylation, carbamidomethylation, and cysteine trioxidation.

Published
2023

20. Supplementary Table 5 from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Mapping of ncMAPs to COSMIC frameshift mutations.

Published
2023

21. Supplementary Table 1 from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Datasets and samples considered in this study.

Published
2023

22. Data from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Tumor antigens can emerge through multiple mechanisms, including translation of noncoding genomic regions. This noncanonical category of tumor antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry (MS) to enable the discovery of noncanonical MHC class I–associated peptides (ncMAP) from noncoding regions. Considering that the emergence of tumor antigens can also involve posttranslational modifications (PTM), we included an open search component in our pipeline. Leveraging the wealth of MS-based immunopeptidomics, we analyzed data from 26 MHC class I immunopeptidomic studies across 11 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant PTMs, using spectral matching and controlled their FDR to 1%. The noncanonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 55%. The data reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive therapeutic targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targets for T-cell therapies or vaccine development.

Published
2023

23. Supplementary figures from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Supplementary Figures S1 to S7.

Published
2023

24. Supplementary legends from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Legends for Supplementary tables, supplementary figures, and supplementary notes.

Published
2023

25. Supplementary notes from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Supplementary notes 1 and 2.

Published
2023

26. Supplementary Table 4 from The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides

Author

Javier A. Alfaro, Sachin Kote, Ted R. Hupp, Robin Fahraeus, Kevin Litchfield, David R. Goodlett, Stefan N. Symeonides, Paul M. Brennan, J. Robert O'Neill, Maciej Parys, Maciej Pawlik, Aleksander Palkowski, David J. Harrison, Ajitha Rajan, Håkan Axelson, Catia Pesquita, Fabio Massimo Zanzotto, Christophe Battail, Alexander Laird, Dominika Bedran, Tongjie Wang, Kenneth Weke, Hans-Christof Gasser, and Georges Bedran

Abstract

Comparison data of COD-dipp ncMAPs with 4 other studies.

Published
2023

27. RNA sequencing of chronic GVHD skin lesions defines shared and unique inflammatory pathways characterizing lichen planus and morphea

Author

Habib Zouali, Juliette Lemasson, Andreea Calugareanu, Christophe Battail, David Michonneau, Hélène le Buanec, Chloé Grolleau, Charles Cassius, Marie Robin, Marine Merandet, Gabor Dobos, Thibault Mahevas, Michel Rybojad, Adèle de Masson, Reyhan Amode, Anne Boland, Laurence Michel, Flore Sicre de Fontbrune, Régis Peffault de Latour, Patrick Bruneval, Hafid Ait-Oufella, Maxime Battistella, Marie Jachiet, Martine Bagot, Jean-François Deleuze, Gérard Socié, and Jean-David Bouaziz

Subjects
Scleroderma, Localized, Sequence Analysis, RNA, Lichen Planus, Graft vs Host Disease, Humans, Hematology, Skin
Abstract

Cutaneous involvement of chronic graft-versus-host disease (cGVHD) has a wide range of manifestations including a lichenoid form with a currently assumed mixed Th1/Th17 signature and a sclerotic form with Th1 signature. Despite substantial heterogeneity of innate and adaptive immune cells recruited to the skin and of the different clinical manifestations, treatment depends mainly on the severity of the skin involvement and relies on systemic, high-dose glucocorticoids alone or in combination with a calcineurin inhibitor. We performed the first study using RNA sequencing to profile and compare the transcriptome of lichen planus cGVHD (n = 8), morphea cGVHD (n = 5), and healthy controls (n = 6). Our findings revealed shared and unique inflammatory pathways to each cGVHD subtype that are both pathogenic and targetable. In particular, the deregulation of IFN signaling pathway was strongly associated with cutaneous cGVHD, whereas the triggering receptor expressed on myeloid cells 1 pathway was found to be specific of lichen planus and likely contributes to its pathogenesis. The results were confirmed at a protein level by performing immunohistochemistry staining and at a transcriptomic level using real-time quantitative polymerase chain reaction.

Published
2022

28. AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Author

Alexandre Bancet, Rita Frem, Florian Jeanneret, Angélique Mularoni, Pauline Bazelle, Caroline Roelants, Jean-Guy Delcros, Jean-François Guichou, Catherine Pillet, Isabelle Coste, Toufic Renno, Christophe Battail, Claude Cochet, Thierry Lomberget, Odile Filhol, and Isabelle Krimm

Abstract

Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric αD pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 αD pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

Published
2022

29. Abstract 6577: CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy

Author

Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, and Javier Alfaro

Subjects
Cancer Research, Oncology
Abstract

Cancer immunotherapy has greatly improved the quality of life of cancer patients and it hinges on the discovery of novel cancer antigens that could be targeted to improve disease outcomes. The creation of databases such as IEDB, SysteMHC, TANTIGEN, caAtlas, HLA Ligand Atlas, Cancer Antigenic Peptide Database, SPENCER and IEAtlas support the immunopeptidomics community in understanding the landscape of antigen presentation. We have developed a pan-cancer, pan-HLA, and pan-tissue database containing immunopeptidomics data mapped to transcriptomic, genomic, immunological and biochemical data. The database was generated from 80 different publicly available immunopeptidomics mass spectrometry datasets collected between 2015-2022 (76 cancer and 4 normal datasets), covering 15 different types of cancers and 152 different HLA-I alleles. The peptides contained in our database were obtained by a combination of closed, open and de novo searches using an in-house developed computational pipeline. Following rigorous false discovery rate estimation at 1% and a second-round search to eliminate any false signals that may not have been detected in the previous round of FDR estimation, we obtained a list of 11.2 million peptide-HLA combinations comprising both coding and non-coding regions of the genome as well as bacterial peptides. These peptides have been mapped to chromosomal coordinates to facilitate adoption by the genomics community of this useful resource on antigen presentation. Pathway/biochemical analysis of each peptide was performed using the rWikiPathways package. Finally, mutations associated with each peptide were annotated using COSMIC and dbSNP resources. Our database includes a FAIR knowledge graph which contextualizes and enriches the data to enable clinicians to take effective therapeutic decisions on the appropriate form of treatment for cancer immunotherapy with the case study of clear cell renal cell carcinoma (ccRCC). We will continue to expand our database with new data over the next two years and expand the scope of its applications to facilitate uptake by the larger scientific community. Citation Format: Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, Javier Alfaro. CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6577.

Published
2023

30. The Immunopeptidome From a Genomic Perspective: Establishing Immune-Relevant Regions for Cancer Vaccine Design

Author

Georges Bedran, Tongjie Wang, Dominika Pankanin, Kenneth Weke, Alexander Laird, Christophe Battail, Fabio Massimo Zanzotto, Catia Pesquita, Håkan Axelson, Ajitha Rajan, David J. Harrison, Aleksander Palkowski, Maciej Pawlik, Maciej Parys, Robert O’Neill, Paul M. Brennan, Stefan Symeonides, David R. Goodlett, Kevin Litchfield, Robin Fahraeus, Ted R. Hupp, Sachin Kote, and Javier A. Alfaro

Abstract

A longstanding disconnect between the growing number of MHC Class I immunopeptidomic studies and genomic medicine hinders cancer vaccine design. We develop COD-dipp to genomically map the full spectrum of detected canonical and non-canonical (non-exonic) MHC Class I antigens from 26 cancer studies. We demonstrate that patient mutations in regions overlapping physically identified antigens better predict immunotherapy response when compared to neoantigen predictions. We suggest a vaccine design approach using 140,966 highly immune-visible regions of the genome annotated by their expression and haplotype frequency in the human population. These regions tend to be highly conserved, mutated in cancer and harbor 7.8 times more immunogenicity. Intersecting pan-cancer mutations with these immune surveilled regions revealed a potential to create off-the-shelf multi-epitope vaccines against public neoantigens. Here we release COD-dipp, a cancer vaccine toolkit as a web-application (https://www.proteogenomics.ca/COD-dipp) and open-source high-throughput resource.

Published
2022

31. NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Author

Padma Murthi, Roland Abi Nahed, Deborah Reynaud, Vincent Sapin, Nadia Alfaidy, Christophe Battail, Mohamed Benharouga, Nicolas Lemaitre, Touria Aboussaouira, Pierre-Adrien Bolze, Wael Traboulsi, Rima Slim, Odile Filhol, Pascale Hoffmann, Houssine Boufettal, Frederic Sergent, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Georgetown University Medical Center, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Centre Hospitalier Universitaire [Grenoble] (CHU), Monash Biomedicine Discovery Institute, Monash University [Clayton], University of Melbourne, McGill University = Université McGill [Montréal, Canada], Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Alfaidy, Nadia, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)

Subjects
0301 basic medicine, Cancer Research, orthotopic model of choriocarcinoma, [SDV.BDLR.RA]Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, Article, Gestational choriocarcinoma, Immune tolerance, Proinflammatory cytokine, NLRP7, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, choriocarcinoma, tumor microenvironment, [SDV.BDLR.RA] Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, reproductive and urinary physiology, RC254-282, Tumor microenvironment, Gene knockdown, business.industry, Choriocarcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, hydatidiform mole, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, business, maternal immune tolerance
Abstract

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC, (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization, and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

Published
2021

32. Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Author

Yann Wallez, Laurent Guyon, Caroline Roelants, Christophe Battail, Q. Franquet, Frédéric Chalmel, Irinka Séraudie, Claude Cochet, Caroline Barette, Odile Filhol, Sofia Giacosa, Nicolas Peilleron, Marie-Odile Fauvarque, Catherine Pillet, Emmanuelle Soleilhac, Clément Sarrazin, Bertrand Evrard, Gaelle Fiard, Jean-Luc Descotes, Jean-Alexandre Long, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Invasion mechanisms in angiogenesis and cancer (IMAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Inovarion, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Genetics and Chemogenomics (GenChem), CHU Grenoble, Gestes Medico-chirurgicaux Assistés par Ordinateur (TIMC-GMCAO), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), UMR1036, Institut National de la Santé et de la Recherche Médicale, 2018, Groupement des Entreprises Françaises dans la lutte contre le Cancer, Isère, Ligue Contre le Cancer, 2017, Association Française d'Urologie, 2019, Centre Hospitalier Universitaire de Grenoble Alpes, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Chard-Hutchinson, Xavier

Subjects
Cancer Research, kinase inhibitor, CK2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, urologic and male genital diseases, lcsh:RC254-282, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, NOX4, 03 medical and health sciences, 0302 clinical medicine, Mediator, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, ROS pathway, tumor tissue slices, 030304 developmental biology, 0303 health sciences, Kinase, ccRCC, apoptosis, Cancer, HIF-2α, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Clear cell renal cell carcinoma, Oncology, Apoptosis, Cell culture, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, ATM, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ex vivo
Abstract

Simple Summary Renal cell carcinoma (RCC) is the eighth leading malignancy in the world, accounting for 4% of all cancers with poor outcome when metastatic. Protein kinases are highly druggable proteins, which are often aberrantly activated in cancers. The aim of our study was to identify candidate targets for metastatic clear cell renal cell carcinoma therapy, using chemo-genomic-based high-throughput screening. We found that the combined inhibition of the CK2 and ATM kinases in renal tumor cells and patient-derived tumor samples induces synthetic lethality. Mechanistic investigations unveil that this drug combination triggers apoptosis through HIF-2α-(Hypoxic inducible factor HIF-2α) dependent reactive oxygen species (ROS) overproduction, giving a new option for patient care in metastatic RCC. Abstract Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

Published
2021

33. Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10

Author

Nihel Berrebeh, Emmanuelle Tillet, Hequn Liu, Christophe Guignabert, Ly Tu, Sabine Bailly, Christophe Battail, Martina Rossi, Nicolas Chaumontel, Marie Ouarné, Laurent Savale, Thomas Daubon, Marc Humbert, Agnès Desroches-Castan, Christine Mallet, Caroline Roelants, Elise Helfer, Claire Bouvard, Pascale Perret, Andreas Bikfalvi, Bailly, Sabine, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Université Paris-Saclay, Invasion mechanisms in angiogenesis and cancer (IMAC), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Inovarion, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-11-INBS-0006,FLI,France Life Imaging(2011), European Project: EQU202003010188,V.A.Cure-814316, DAUBON, Thomas, BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel - - B9inPAH2017 - ANR-17-CE14-0006 - AAPG2017 - VALID, IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, H2020 MarieSkłodowska-Curie Actions - V.A.Cure-814316 - EQU202003010188 - INCOMING, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre chirurgical Marie Lannelongue, and Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, Activin Receptors, Type II, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, pulmonary hypertension, Growth Differentiation Factor 2, medicine, bone morphogenetic proteins, Animals, Hypoxia, Lung, Mice, Knockout, Endothelin receptor antagonist, business.industry, medicine.disease, Pulmonary hypertension, Bosentan, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], vascular anomalies, Phenotype, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, high-output heart failure, Heart failure, Knockout mouse, Vascular resistance, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Vasoconstriction, pulmonary vascular remodeling, medicine.drug
Abstract

Aims BMP9 and BMP10 mutations were recently identified in patients with pulmonary arterial hypertension, but their specific roles in the pathogenesis of the disease are still unclear. We aimed to study the roles of BMP9 and BMP10 in cardiovascular homeostasis and pulmonary hypertension using transgenic mouse models deficient in Bmp9 and/or Bmp10. Methods and results Single- and double-knockout mice for Bmp9 (constitutive) and/or Bmp10 (tamoxifen inducible) were generated. Single-knock-out (KO) mice developed no obvious age-dependent phenotype when compared with their wild-type littermates. However, combined deficiency in Bmp9 and Bmp10 led to vascular defects resulting in a decrease in peripheral vascular resistance and blood pressure and the progressive development of high-output heart failure and pulmonary hemosiderosis. RNAseq analysis of the lungs of the double-KO mice revealed differential expression of genes involved in inflammation and vascular homeostasis. We next challenged these mice to chronic hypoxia. After 3 weeks of hypoxic exposure, Bmp10-cKO mice showed an enlarged heart. However, although genetic deletion of Bmp9 in the single- and double-KO mice attenuated the muscularization of pulmonary arterioles induced by chronic hypoxia, we observed no differences in Bmp10-cKO mice. Consistent with these results, endothelin-1 levels were significantly reduced in Bmp9 deficient mice but not Bmp10-cKO mice. Furthermore, the effects of BMP9 on vasoconstriction were inhibited by bosentan, an endothelin receptor antagonist, in a chick chorioallantoic membrane assay. Conclusions Our data show redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions (only combined deletion of both Bmp9 and Bmp10 was associated with severe defects) but highlight specific roles under chronic hypoxic conditions. We obtained evidence that BMP9 contributes to chronic hypoxia-induced pulmonary vascular remodelling, whereas BMP10 plays a role in hypoxia-induced cardiac remodelling in mice.

Published
2021

34. Region-specific expression of young small-scale duplications in the human central nervous system

Author

Vincent Meyer, Christophe Battail, Solène Brohard-Julien, Jean-François Deleuze, Vincent Frouin, Edith Le Floch, Smahane Chalabi, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Unité Analyse et Traitement de l'Information (UNATI), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA))

Subjects
Central Nervous System, Scale (anatomy), Gene co-expression network, Evolution, [SDV]Life Sciences [q-bio], Central nervous system, Biology, Genome, Transcriptome, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Genes, Duplicate, Gene Duplication, Gene duplication, Gene expression, medicine, QH359-425, Humans, Brain region-specific expression, Gene, QH540-549.5, 030304 developmental biology, Small scale duplication, 0303 health sciences, Ecology, Human central nervous system, Paralog, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], medicine.anatomical_structure, Expression (architecture), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evolutionary biology, 030217 neurology & neurosurgery, Research Article
Abstract

BackgroundThe duplication of genes is one of the main genetic mechanisms that led to the gain in complexity of biological tissue. Although the implication of duplicated gene expression in brain evolution was extensively studied through comparisons between organs, their role in the regional specialization of the adult human central nervous system has not yet been well described.ResultsOur work explored intra-organ expression properties of paralogs through multiple territories of the human central nervous system (CNS) using transcriptome data generated by the Genotype-Tissue Expression (GTEx) consortium. Interestingly, we found that paralogs were associated with region-specific expression in CNS, suggesting their involvement in the differentiation of these territories. Beside the influence of gene expression level on region-specificity, we observed the contribution of both duplication age and duplication type to the CNS region-specificity of paralogs. Indeed, we found that small scale duplicated genes (SSDs) and in particular ySSDs (SSDs younger than the 2 rounds of whole genome duplications) were more CNS region-specific than other paralogs. Next, by studying the two paralogs of ySSD pairs, we observed that when they were region-specific, they tend to be specific to the same region more often than for other paralogs, showing the high co-expression of ySSD pairs. Extension of this analysis to families of paralogs showed that the families with co-expressed gene members (i.e. homogeneous families) were enriched in ySSDs. Furthermore, these homogeneous families tended to be region-specific families, where the majority of their gene members were specifically expressed in the same region.ConclusionsOverall, our study suggests the major involvement of ySSDs in the differentiation of human central nervous system territories. Therefore, we show the relevance of exploring region-specific expression of paralogs at the intra-organ level.

Published
2020

35. Gene expression and response prediction to amisulpride in the OPTiMiSE first episode psychoses

Author

Dan Rujescu, Marion Leboyer, Delphine Bacq-Daian, Stéphane Jamain, Philip McGuire, Jean-François Deleuze, Réjane Troudet, Caroline Barau, René S. Kahn, Wafa Bel Haj Ali, Inge van Rossum, Christophe Battail, Anne Boland-Auge, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], Centre National de Recherche en Génomique Humaine [Évry] (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Plateforme de Ressources Biologiques [Henri Mondor AP-HP, Créteil] (PRB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Martin-Luther-Universität Halle Wittenberg (MLU), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Icahn School of Medicine at Mount Sinai [New York] (MSSM), OPTiMiSE study group: Inge Winter van Rossum, Dan Rujescu, Philip McGuire, René S Kahn, Marion Leboyer, Stéphane Jamain, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], and Jamain, Stéphane

Subjects
Oncology, medicine.medical_specialty, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Gene Expression, Article, 03 medical and health sciences, 0302 clinical medicine, Text mining, Management of schizophrenia, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, medicine, Humans, Amisulpride, Pharmacology, First episode, business.industry, Significant difference, medicine.disease, 030227 psychiatry, 3. Good health, Gene expression profiling, Europe, Psychiatry and Mental health, Treatment Outcome, Psychotic Disorders, Schizophrenia, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], business, 030217 neurology & neurosurgery, medicine.drug, Antipsychotic Agents
Abstract

International audience; A fundamental shortcoming in the current treatment of schizophrenia is the lack of valid criteria to predict who will respond to antipsychotic treatment. The identification of blood-based biological markers of the therapeutic response would enable clinicians to identify the subgroup of patients in whom conventional antipsychotic treatment is ineffective and offer alternative treatments. As part of the Optimisation of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) programme, we conducted an RNA-Seq analysis on 188 subjects with first episode psychosis, all of whom were subsequently treated with amisulpride for 4 weeks. We compared gene expression on total RNA from patients' blood before and after treatment and identified 32 genes for which the expression changed after treatment in good responders only. These findings were replicated in an independent sample of 24 patients with first episode psychosis. Six genes showed a significant difference in expression level between good and poor responders before starting treatment, allowing to predict treatment outcome with a predictive value of 93.8% when combined with clinical features. Collectively, these findings identified new mechanisms to explain symptom improvement after amisulpride medication and highlight the potential of combining gene expression profiling with clinical data to predict treatment response in first episode psychoses.

Published
2020

36. Multi-omic analysis of gametogenesis reveals a novel signature at the promoters and distal enhancers of active genes

Author

Christophe Battail, Sylvie Kieffer-Jaquinod, Laila El Khattabi, Melina Blanco, Sara El Kennani, Anne-Marie Hesse, Samuel Terrier, François Fenaille, Delphine Pflieger, Emmanuelle Lastrucci, Annelaure Damont, Sophie Chantalat, Jérôme Govin, Christophe Bruley, Mathilde Louwagie, Côme Ialy-Radio, Marion Crespo, Julie Cocquet, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Biologie François JACOB (JACOB), Université Paris-Saclay, Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ANR-17-CE12-0004,CHROMATOZOA,(Dé)régulation génique et chromatinienne pendant la spermiogénèse: acteurs & conséquences sur la descendance(2017), and PFLIEGER, Delphine

Subjects
Male, Proteomics, Transcription, Genetic, AcademicSubjects/SCI00010, Data Resources and Analyses, Biology, Epigenesis, Genetic, Histones, 03 medical and health sciences, Histone H3, 0302 clinical medicine, Acetyl Coenzyme A, Yeasts, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Animals, Metabolomics, Histone code, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Promoter Regions, Genetic, Spermatogenesis, Enhancer, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Lysine, Acetylation, Genomics, Biological Evolution, Cell biology, Chromatin, Histone Code, Mice, Inbred C57BL, Enhancer Elements, Genetic, Histone, CTCF, Crotonates, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Acyl Coenzyme A, 030217 neurology & neurosurgery
Abstract

Epigenetic regulation of gene expression is tightly controlled by the dynamic modification of histones by chemical groups, the diversity of which has largely expanded over the past decade with the discovery of lysine acylations, catalyzed from acyl-coenzymes A. We investigated the dynamics of lysine acetylation and crotonylation on histones H3 and H4 during mouse spermatogenesis. Lysine crotonylation appeared to be of significant abundance compared to acetylation, particularly on Lys27 of histone H3 (H3K27cr) that accumulates in sperm in a cleaved form of H3. We identified the genomic localization of H3K27cr and studied its effects on transcription compared to the classical active mark H3K27ac at promoters and distal enhancers. The presence of both marks was strongly associated with highest gene expression. Assessment of their co-localization with transcription regulators (SLY, SOX30) and chromatin-binding proteins (BRD4, BRDT, BORIS and CTCF) indicated systematic highest binding when both active marks were present and different selective binding when present alone at chromatin. H3K27cr and H3K27ac finally mark the building of some sperm super-enhancers. This integrated analysis of omics data provides an unprecedented level of understanding of gene expression regulation by H3K27cr in comparison to H3K27ac, and reveals both synergistic and specific actions of each histone modification.

Published
2020

37. Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

Author

Jonathan Lopez, Christophe Battail, François Golfier, Fabienne Allias, Pierre-Adrien Bolze, Constance Collet, Benoit You, Mojgan Devouassoux-Shisheboran, Nadia Alfaidy, Touria Hajri, François Mallet, Jérôme Massardier, Nicolas Lemaître, Sophie Patrier, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire [Grenoble] (CHU), Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Rouen, Normandie Université (NU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), BIOMERIEUX, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université de Lyon-Université de Lyon, Hôpital Edouard Herriot [CHU - HCL], Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alfaidy, Nadia, and Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3)

Subjects
placenta, QH301-705.5, Angiogenesis, Medicine (miscellaneous), Biology, Article, General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Gestational choriocarcinoma, 03 medical and health sciences, 0302 clinical medicine, SALL4, Placenta, gestational trophoblastic neoplasia, choriocarcinoma, medicine, gestational trophoblastic disease, Biology (General), reproductive and urinary physiology, 030304 developmental biology, transforming growth factor beta, 0303 health sciences, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Gestational trophoblastic disease, Choriocarcinoma, Trophoblast, Transforming growth factor beta, medicine.disease, trophoblast, female genital diseases and pregnancy complications, 3. Good health, hydatidiform mole, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, biology.protein
Abstract

International audience; The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets.

Published
2021

38. Comprehensive analysis of RNA-seq kits for standard, low and ultra-low quantity samples

Author

Christophe Ambroise, Solène Brohard-Julien, Christophe Battail, Jean-François Deleuze, Robert Olaso, Eric Bonnet, Céline Derbois, Marie-Ange Palomares, and Cyril Dalmasso

Subjects
Transcriptome, Gene expression profiling, Reference tissue, Low input, Gene expression, RNA, RNA-Seq, Computational biology, Gold standard (test), Biology
Abstract

High-throughput RNA-sequencing has become the gold standard method for whole-transcriptome gene expression analysis, and is widely used in numerous applications to study cell and tissue transcriptomes. It is also being increasingly used in a number of clinical applications, including expression profiling for diagnostics and alternative transcript detection. However, despite its many advantages, RNA sequencing can be challenging in some situations, for instance in cases of low input amounts or degraded RNA samples. Several protocols have been proposed to overcome these challenges, and many are available as commercial kits. In this study, we comprehensively test three recent commercial technologies for RNA-seq library preparation (TruSeq, SMARTer and SMARTer Ultra-Low) on human reference tissue preparations, using standard (1μg), low (100 and 10 ng) and ultra-low (< 1 ng) input amounts, and for mRNA and total RNA, stranded or unstranded. The results are analyzed using read quality and alignment metrics, gene detection and differential gene expression metrics. Overall, we show that the TruSeq kit performs well with an input amount of 100 ng, while the SMARTer kit shows degraded performance for inputs of 100 and 10 ng, and the SMARTer Ultra-Low kit performs relatively well for input amounts < 1 ng. All the results are discussed in detail, and we provide guidelines for biologists for the selection of a RNA-seq library preparation kit.

Published
2019

39. Gene flow contributes to diversification of the major fungal pathogen $Candida\ albicans$

Author

Marie-Elisabeth Bougnoux, Gavin Sherlock, Patrick Wincker, Marina Marcet-Houben, Emmanuelle Permal, Toni Gabaldón, Dorothée Diogo, Christophe Battail, Natacha Sertour, Patrice Le Pape, Laurence Ma, Jong Hee Shin, Andrew M. Borman, Julie Poulain, Robin C. May, Jeanne Ropars, Soo Hyun Kim, Christiane Bouchier, Kevin Mosca, Shangrong Fan, Christophe d'Enfert, Corinne Maufrais, Kerstin Voelz, Orazio Romeo, Guillaume Laval, Anuradha Chowdhary, Aurélie Perin, Katja Schwartz, Ecologie Systématique et Evolution (ESE), Université Paris-Sud - Paris 11 (UP11)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques, Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Universitat Pompeu Fabra [Barcelona], Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), Génétique Evolutive Humaine - Human Evolutionary Genetics, Génomique (Plate-Forme), Institut Pasteur [Paris], Centre de Recherche et Innovation Technologique (CITECH), Stanford University [Stanford], University of Birmingham [Birmingham], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Public Health England [London], University of Delhi, Peking University [Beijing], Chonnam National University [Gwangju], Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), University of Messina, Centro Neurolesi Bonino Pulejo Messina (IRCCS Messina), Centro de Regulación Genómica (CRG), ICREA Infection Biology Laboratory (Department of Experimental and Health Sciences), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], the Genoscope (projet #15 AP2008/2009 SNP C. albicans) and the Swiss National Science Foundation (Sinergia CRSII5_173863/1) to C.E., J.R. was supported by a Pasteur-Roux fellowship from Institut Pasteur. D.D. was the recipient of a PhD fellowship from Institut National de la Recherche Agronomique. E.P. was the recipient of a post-doctoral fellowship from the Wellcome Trust (WT088858MA). M.M.-H. and T.G. were supported by a grant from the Spanish Ministry of Economy and Competitiveness, BFU2015–67107 cofunded by the European Regional Development Fund (ERDF). C.E., M.-E.B., S.H.K., and J.H.S. were supported by a grant from the French and Korean Ministries for Foreign Affairs (PHC STAR 2011 25841YA). R.C.M. was supported by project MitoFun, funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement No. 614562 and by a Wolfson Research Merit Award from the Royal Society. R.C.M. and K.V. were funded by the Surgical Reconstruction and Microbiology Research Centre, which is supported by the National Institute of Health Research, UK. G.S. was supported by the NIH grants R01-HG003468 and RO1-DE015873. C.E. and T.G. are members of the CNRS GDRI 0814 iGenolevures consortium. High-throughput sequencing has been performed on the Genomics Platform, member of France Génomique consortium (ANR10-INBS-09-08)., We thank Bernard Dujon and Tatiana Giraud for providing insights on an earlier version of this manuscript., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 614562,EC:FP7:ERC,ERC-2013-CoG,MITOFUN(2014), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universitat Pompeu Fabra [Barcelona] (UPF), Génomique (Plate-Forme) - Genomics Platform, Institut Pasteur [Paris] (IP), Stanford University, Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, Gene Flow, Lineage (genetic), Population genetics, Science, [SDV]Life Sciences [q-bio], Genes, Fungal, education, General Physics and Astronomy, Virulence, Loss of Heterozygosity, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Linkage Disequilibrium, Gene flow, 03 medical and health sciences, Gene Frequency, Species Specificity, Candida albicans, Humans, lcsh:Science, Phylogeny, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Genetics, Genetic diversity, Multidisciplinary, biology, Whole Genome Sequencing, Candidiasis, Genetic Variation, General Chemistry, biology.organism_classification, Corpus albicans, 3. Good health, 030104 developmental biology, GENERATION SEQUENCING DATA, VULVO-VAGINAL CANDIDIASIS, PARASEXUAL CYCLE, MOLECULAR PHYLOGENETICS, CLINICAL STRAINS, DUBLINIENSIS, AFRICANA, REVEALS, YEAST, DNA, Microbial genetics, lcsh:Q, Pathogens
Abstract

Elucidating population structure and levels of genetic diversity and recombination is necessary to understand the evolution and adaptation of species. Candida albicans is the second most frequent agent of human fungal infections worldwide, causing high-mortality rates. Here we present the genomic sequences of 182 C. albicans isolates collected worldwide, including commensal isolates, as well as ones responsible for superficial and invasive infections, constituting the largest dataset to date for this major fungal pathogen. Although, C. albicans shows a predominantly clonal population structure, we find evidence of gene flow between previously known and newly identified genetic clusters, supporting the occurrence of (para)sexuality in nature. A highly clonal lineage, which experimentally shows reduced fitness, has undergone pseudogenization in genes required for virulence and morphogenesis, which may explain its niche restriction. Candida albicans thus takes advantage of both clonality and gene flow to diversify., The fungal pathogen Candida albicans can undergo a parasexual process that may contribute to genetic diversity, but its actual relevance is unclear. Here, Ropars et al. analyse the genomic sequences of 182 C. albicans isolates collected worldwide and find evidence of gene flow and thus parasexuality in nature.

Published
2018

40. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

Author

Christophe Battail, Mark A. Tarnopolsky, Jean-François Deleuze, Magdalena Matloka, Arnaud Jollet, Arnaud F. Klein, Naira Naouar, Anne Boland, Frédérique Edom-Vovard, Micaela Polay Espinoza, Audrey Bazinet, Frédérique Rau, Jack Puymirat, Kamel Mamchaoui, Denis Furling, Ludovic Arandel, Vincent Mouly, Damily De Dea Diniz, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), McMaster University [Hamilton, Ontario], Centre hospitalier universitaire de Québec (CHUQ), Centre Hospitalier Universitaire de Québec, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Muscle Fibers, Skeletal, Myotonic dystrophy, Drug Evaluation, Preclinical, Medicine (miscellaneous), lcsh:Medicine, medicine.disease_cause, Immunology and Microbiology (miscellaneous), Expanded repeats, Myocyte, Child, Cell Line, Transformed, Mutation, Nuclear aggregates, Middle Aged, 3. Good health, Cell biology, RNA splicing, Muscle cell line, Female, lcsh:RB1-214, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Therapeutic compounds, Neuroscience (miscellaneous), Context (language use), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, lcsh:Pathology, Humans, Resource Article, Muscle, Skeletal, MyoD Protein, Alternative splicing, lcsh:R, RNA, Fibroblasts, Oligonucleotides, Antisense, medicine.disease, Dd, Molecular biology, 030104 developmental biology, Cell culture, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations., Summary: Myotonic dystrophy muscle cell models displaying characteristic disease-associated molecular features can be used to investigate molecular pathophysiological mechanisms and evaluate therapeutic approaches.

Published
2017

41. The Arabidopsis hnRNP-Q Protein LIF2 and the PRC1 subunit LHP1 function in concert to regulate the transcription of stress-responsive genes

Author

Mélanie Hachet, Anne M. Molitor, David Latrasse, Philippe Andrey, Christophe Battail, Matthias Zytnicki, Valérie Gaudin, Stefania Del Prete, Hadi Quesneville, Adriana Alberti, Nicole Houba-Hérin, Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), UPMC - UFR Sciences de la vie (UFR 927 ), Université Pierre et Marie Curie - Paris 6 (UPMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Molitor, Anne M., Latrasse, David, Zytnicki, Matthias, Gaudin, Valérie, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, endocrine system, Heterogeneous nuclear ribonucleoprotein, Heterochromatin, [SDV]Life Sciences [q-bio], Plant Science, 03 medical and health sciences, Transcription (biology), Arabidopsis, [SDV.IDA]Life Sciences [q-bio]/Food engineering, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, ribonucléoprotéine, Gene, Research Articles, Genetics, Regulation of gene expression, biology, arabidopsis thaliana, Cell Biology, biology.organism_classification, Chromatin, 030104 developmental biology, Histone, protéine, biology.protein, transcription
Abstract

Advance Publication; International audience; LHP1-INTERACTING FACTOR2 (LIF2), a heterogeneous nuclear ribonucleoprotein involved in Arabidopsis thaliana cell fate and stress responses, interacts with LIKE HETEROCHROMATIN PROTEIN1 (LHP1), a Polycomb Repressive Complex1 (PRC1) subunit. To investigate LIF2-LHP1 functional interplay, we mapped their genome-wide distributions in wild-type, lif2, and lhp1 backgrounds, under standard and stress conditions. Interestingly, LHP1-targeted regions form local clusters, suggesting an underlying functional organization of the plant genome. Regions targeted by both LIF2 and LHP1 were enriched in stress-responsive genes, the H2A.Z histone variant, and antagonistic histone marks. We identified specific motifs within the targeted regions, including a G-box-like motif, a GAGA motif, and a telo-box. LIF2 and LHP1 can operate both antagonistically and synergistically. In response to methyl jasmonate treatment, LIF2 was rapidly recruited to chromatin, where it mediated transcriptional gene activation. Thus, LIF2 and LHP1 participate in transcriptional switches in stress-response pathways.

Published
2016

42. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin

Author

Anne Boland, Jean-François Deleuze, Sandrine Baghdoyan, Cécile Martinat, Sylvia Franc, Emilie Chautard, Marc Peschanski, Christophe Battail, Xavier Nissan, François Artiguenave, Laetitia Barrault, Jacqueline Gide, Pierre Rustin, Guillaume Charpentier, Clara Benoit, Didier Auboeuf, Paule Bénit, Guillaume Bassez, Delphine Laustriat, Denis Furling, Centre d'Etude des Cellules Souches (CECS), AFM, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon] - Université Claude Bernard Lyon 1 (UCBL) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive (LBBE), Université Claude Bernard Lyon 1 (UCBL) - Institut National de Recherche en Informatique et en Automatique (Inria) - Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuroprotection du Cerveau en Développement (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Robert Debré - Université Paris Diderot - Paris 7 (UP7) - Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Université Paris Diderot - Paris 7 (UP7), Centre d'études et de recherches pour l'intensification du traitement du diabète (CERITD), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC) - AFM - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - IFR10, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Evry-Val d'Essonne - Institut National de la Santé et de la Recherche Médicale (INSERM), Association française contre les myopathies (AFM-Téléthon), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
AMPK, medicine.drug_class, RBM3, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Myotonic dystrophy, 03 medical and health sciences, alternative splicing, 0302 clinical medicine, Downregulation and upregulation, Drug Discovery, medicine, myotonic dystrophy type 1, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biguanide, lcsh:RM1-950, Alternative splicing, medicine.disease, Metformin, 3. Good health, lcsh:Therapeutics. Pharmacology, Mechanism of action, RNA splicing, Cancer research, Molecular Medicine, Original Article, medicine.symptom, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.

Published
2015

43. Erratum for the Report: 'Early allopolyploid evolution in the post-Neolithic Brassica napus oilseed genome' by B. Chalhoub, F. Denoeud, S. Liu, I. A. P. Parkin, H. Tang, X. Wang, J. Chiquet, H. Belcram, C. Tong, B. Samans, M. Corréa, C. Da Silva, J. Just, C. Falentin, C. S. Koh, I. Le Clainche, M. Bernard, P. Bento, B. Noel, K. Labadie, A. Alberti, M. Charles, D. Arnaud, H. Guo, C. Daviaud, S. Alamery, K. Jabbari, M. Zhao, P. P. Edger, H. Chelaifa, D. Tack, G. Lassalle, I. Mestiri, N. Schnel, M.-C. Le Paslier, G. Fan, V. Renault, P. E. Bayer, A. A. Golicz, S. Manoli, T.-H. Lee, V. Ha Dinh Thi, S. Chalabi, Q. Hu, C. Fan, R. Tollenaere, Y. Lu, C. Battail, J. Shen, C. H. D. Sidebottom, X. Wang, A. Canaguier, A. Chauveau, A. Bérard, G. Deniot, M. Guan, Z. Liu, F. Sun, Y. P. Lim, E. Lyons, C. D. Town, I. Bancroft, X. Wang, J. Meng, J. Ma, J. C. Pires, G. J. King, D. Brunel, R. Delourme, M. Renard, J.-M. Aury, K. L. Adams, J. Batley, R. J. Snowdon, J. Tost, D. Edwards, Y. Zhou, W. Hua, A. G. Sharpe, A. H. Paterson, C. Guan, P. Wincker

Author

Aurélie Canaguier, Christophe Battail, Jean-Marc Aury, Christopher D. Town, Christian Daviaud, David C. Tack, Wei Hua, Christine Sidebottom, Shengyi Liu, Reece Tollenaere, Sahana Manoli, Graham J.W. King, Fengming Sun, J. Shen, Victor Renault, Philipp E. Bayer, I. Le Clainche, Jacqueline Batley, Ian Bancroft, Nicolas Schnel, M. C. Le Paslier, Dominique Arnaud, Karine Labadie, Agnieszka A. Golicz, Dominique Brunel, Smahane Chalabi, Hui Guo, Yongming Zhou, Eric Lyons, Pascal Bento, Gilles Lassalle, Chunyun Guan, Yong Pyo Lim, Imen Mestiri, J. C. Pires, Guangyi Fan, Houda Chelaifa, Mei Guan, Tae-Ho Lee, Harry Belcram, Qiong Hu, F. Denoeud, Aurélie Chauveau, Andrew G. Sharpe, Bernard Noël, Boulos Chalhoub, Chaobo Tong, Adriana Alberti, Patrick Wincker, Jinling Meng, Birgit Samans, Patrick P. Edger, C. Da Silva, Margot Correa, Jianxin Ma, Régine Delourme, Keith L. Adams, Meixia Zhao, Haibao Tang, David Edwards, Andrew H. Paterson, Cyril Falentin, Zhongsong Liu, Julien Chiquet, Y. Lu, Xinfa Wang, Jérémy Just, V. Ha Dinh Thi, Kamel Jabbari, Chuchuan Fan, G. Deniot, Rod J. Snowdon, Jörg Tost, Aurélie Bérard, Mathieu Charles, Michel Renard, Salman Alamery, Maria Bernard, Isobel A. P. Parkin, and Chu Shin Koh

Subjects
Multidisciplinary, Botany, Brassica, Biology, biology.organism_classification, Genome
Published
2014

44. Plant genetics. Early allopolyploid evolution in the post-Neolithic Brassica napus oilseed genome

Author

Boulos, Chalhoub, France, Denoeud, Shengyi, Liu, Isobel A P, Parkin, Haibao, Tang, Xiyin, Wang, Julien, Chiquet, Harry, Belcram, Chaobo, Tong, Birgit, Samans, Margot, Corréa, Corinne, Da Silva, Jérémy, Just, Cyril, Falentin, Chu Shin, Koh, Isabelle, Le Clainche, Maria, Bernard, Pascal, Bento, Benjamin, Noel, Karine, Labadie, Adriana, Alberti, Mathieu, Charles, Dominique, Arnaud, Hui, Guo, Christian, Daviaud, Salman, Alamery, Kamel, Jabbari, Meixia, Zhao, Patrick P, Edger, Houda, Chelaifa, David, Tack, Gilles, Lassalle, Imen, Mestiri, Nicolas, Schnel, Marie-Christine, Le Paslier, Guangyi, Fan, Victor, Renault, Philippe E, Bayer, Agnieszka A, Golicz, Sahana, Manoli, Tae-Ho, Lee, Vinh Ha Dinh, Thi, Smahane, Chalabi, Qiong, Hu, Chuchuan, Fan, Reece, Tollenaere, Yunhai, Lu, Christophe, Battail, Jinxiong, Shen, Christine H D, Sidebottom, Xinfa, Wang, Aurélie, Canaguier, Aurélie, Chauveau, Aurélie, Bérard, Gwenaëlle, Deniot, Mei, Guan, Zhongsong, Liu, Fengming, Sun, Yong Pyo, Lim, Eric, Lyons, Christopher D, Town, Ian, Bancroft, Xiaowu, Wang, Jinling, Meng, Jianxin, Ma, J Chris, Pires, Graham J, King, Dominique, Brunel, Régine, Delourme, Michel, Renard, Jean-Marc, Aury, Keith L, Adams, Jacqueline, Batley, Rod J, Snowdon, Jorg, Tost, David, Edwards, Yongming, Zhou, Wei, Hua, Andrew G, Sharpe, Andrew H, Paterson, Chunyun, Guan, and Patrick, Wincker

Subjects
Evolution, Molecular, Polyploidy, Brassica napus, Chromosome Duplication, Seeds, Genome, Plant
Abstract

Oilseed rape (Brassica napus L.) was formed ~7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72× genome multiplication since the origin of angiosperms and high gene content. We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement.

Published
2014

45. Early allopolyploid evolution in the post-Neolithic[i] Brassica napus[/i] oilseed genome

Author

Patrick Wincker, Pascal Bento, Sahana Manoli, Agnieszka A. Golicz, G. Deniot, Shengyi Liu, Christine Sidebottom, Chu Shin Koh, Ian Bancroft, Christian Daviaud, David C. Tack, Rod J. Snowdon, Jörg Tost, Guangyi Fan, Hui Guo, Smahane Chalabi, Boulos Chalhoub, Xinfa Wang, Harry Belcram, Aurélie Chauveau, Gilles Lassalle, Jean-Marc Aury, Tae-Ho Lee, Houda Chelaifa, Jinling Meng, Christopher D. Town, Haibao Tang, Zhongsong Liu, Julien Chiquet, Andrew G. Sharpe, Salman Alamery, Chunyun Guan, Mathieu Charles, Qiong Hu, Xiyin Wang, Xiaowu Wang, Jianxin Ma, Régine Delourme, Mei Guan, Eric Lyons, Chaobo Tong, Margot Correa, Adriana Alberti, Keith L. Adams, Patrick P. Edger, Marie-Christine Le Paslier, Yunhai Lu, Corinne Da Silva, Christophe Battail, Andrew H. Paterson, Isabelle Le Clainche, Benjamin Noel, Jérémy Just, Jacqueline Batley, Jinxiong Shen, Fengming Sun, Kamel Jabbari, Karine Labadie, Michel Renard, Maria Bernard, Birgit Samans, Aurélie Canaguier, Isobel A. P. Parkin, Yong Pyo Lim, Vinh Ha Dinh Thi, Victor Renault, Meixia Zhao, David Edwards, Graham J.W. King, Nicolas Schnel, Dominique Brunel, Cyril Falentin, Reece Tollenaere, Aurélie Bérard, Yongming Zhou, Dominique Arnaud, Imen Mestiri, Philippe E. Bayer, Chuchuan Fan, Wei Hua, J. Chris Pires, Unité de recherche en génomique végétale (URGV), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Oil Crops Research Institute, Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture-Chinese Academy of Agricultural Sciences (CAAS), Agriculture and Agri-Food (AAFC), J. Craig Venter Institute [La Jolla, USA] (JCVI), Center for Genomics and Biotechnology, Fujian Agriculture and Forestry University (FAFU), University of Georgia [USA], School of Life Sciences, Center of Genomics and Computational Biology, Hebei United University, Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Research Center for Biosystems, Land Use and Nutrition, Department of Plant Breeding, Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-AGROCAMPUS OUEST, National Research Council of Canada (NRC), Etude du Polymorphisme des Génomes Végétaux (EPGV), Institut National de la Recherche Agronomique (INRA), Centre National de Genotypage, Plant Genome Mapping Laboratory, Laboratoire épigénétique et environnement, School of Agriculture and Food Sciences, Australian Centre for Plant Functional Genomics, University of Queensland [Brisbane], Cologne Center for Genomics, University of Cologne, Department of Agronomy, Purdue University [West Lafayette], Department of Plant and Microbial Biology, University of California (UC), Department of Botany [Vancouver] (UBC Botany), University of British Columbia (UBC), National Key Laboratory of Crop Genetic Improvement [China], Huazhong Agricultural University [Wuhan] (HZAU), Beijing Genome Institute, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, College of Agronomy, Hunan Agricultural University [Changsha], Department of Horticulture, Molecular Genetics and Genomics Laboratory, Chungnam National University (CNU), School of Plant Sciences, iPlant Collaborative, University of Arizona, Department of Biology, University of York [York, UK], Institute of Vegetables and Flowers (IVF), Chinese Academy of Agricultural Sciences (CAAS), Division of Biological Sciences, University of Missouri [Columbia] (Mizzou), University of Missouri System-University of Missouri System, Southern Cross Plant Science, Southern Cross University (SCU), School of Plant Biology, The University of Western Australia (UWA), Laboratory for Epigenetics and Environment, Agriculture and Agri-Food [Ottawa] (AAFC), Laboratoire de Mathématiques et Modélisation d'Evry, Justus-Liebig-Universität Gießen (JLU), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of California, Huazhong Agricultural University, Euralis Semences, Écologie et santé des écosystèmes (ESE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), BIOGEMMA, Unité de Recherches Zootechniques (URZ), De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut national de recherches archéologiques préventives (Inrap), Limagrain, J. Craig Venter Institute, Fujian Agriculture and Forestry University, Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of Botany, University of Missouri [Columbia], Southern Cross University, Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), UMR 1165 Unité de Recherche en Génomique Végétale, Institut National de la Recherche Agronomique ( INRA ) -Université d'Evry Val d'Essonne, Génomique métabolique ( UMR 8030 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Ministry of Agriculture-Chinese Academy of Agricultural Sciences ( CAAS ), Agriculture and Agri-Food [Ottawa] ( AAFC ), University of Georgia, Laboratoire de Mathématiques et Modélisation d'Evry ( LaMME ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -ENSIIE-Centre National de la Recherche Scientifique ( CNRS ), Unité de recherche en génomique végétale ( URGV ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -Centre National de la Recherche Scientifique ( CNRS ), Justus Liebig University Giessen, Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Génétique, Environnement et Protection des Plantes ( IGEPP ), Institut National de la Recherche Agronomique ( INRA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST, National Research Council of Canada ( NRC ), Etude du Polymorphisme des Génomes Végétaux ( EPGV ), Institut National de la Recherche Agronomique ( INRA ), University of British Columbia ( UBC ), National Key Laboratory of Crop Genetic Improvement, Chungnam National University, Institute of Vegetables and Flowers ( IVF ), Chinese Academy of Agricultural Sciences ( CAAS ), University of Missouri ( Saisissez le sigle en majuscules sans points ), The University of Western Australia ( UWA ), AGROCAMPUS OUEST-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA)

Subjects
0106 biological sciences, plant genome, [SDV]Life Sciences [q-bio], Brassica, rapeseed, Biology, 01 natural sciences, Genome, Evolution, Molecular, Polyploidy, 03 medical and health sciences, chemistry.chemical_compound, Gene duplication, genetics, Epigenetics, Domestication, Gene, 030304 developmental biology, 2. Zero hunger, Genetics, 0303 health sciences, Multidisciplinary, [ SDV ] Life Sciences [q-bio], molecular evolution, Brassica napus, chromosome duplication, food and beverages, plant seed, biology.organism_classification, chemistry, Glucosinolate, Seeds, cytology, Genome, Plant, 010606 plant biology & botany
Abstract

Oilseed rape (Brassica napus L.) was formed ∼7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72x genome multiplication since the origin of angiosperms and high gene content.We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement., Erratum published in Vol 345, no. 6202 September 2014 DOI: 10.1126/science.1260782

Published
2014

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