33 results on '"Agustin F. Fernández"'
Search Results
2. Generation of a human iPSC line from a patient with an optic atrophy ‘plus’ phenotype due to a mutation in the OPA1 gene
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Teresa Galera-Monge, Francisco Zurita-Díaz, Ana Moreno-Izquierdo, Mario F. Fraga, Agustin F. Fernández, C. Ayuso, Rafael Garesse, and M. Esther Gallardo
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Biology (General) ,QH301-705.5 - Abstract
Human iPSC line Oex2054SV.4 was generated from fibroblasts of a patient with an optic atrophy ‘plus’ phenotype associated with a heterozygous mutation in the OPA1 gene. Reprogramming factors OCT3/4, SOX2, CMYC and KLF4 were delivered using a non-integrative methodology that involves the use of Sendai virus. more...
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- 2016
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3. Data from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
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Victor Moreno, Manel Esteller, Gabriel Capellá, Jordi Guardiola, Mario F. Fraga, Alberto Villanueva, Ramón Salazar, Francisco Rodriguez-Moranta, Javier de Oca, Sebastiano Biondo, Agustin F. Fernández, Antonio Berenguer-Llergo, Daniel Azuara, and F. Javier Carmona more...
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DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established.In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples.Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%–89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients.This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD. Cancer Prev Res; 6(7); 656–65. ©2013 AACR. more...
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- 2023
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4. Supplementary Figures 1-6 from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
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Victor Moreno, Manel Esteller, Gabriel Capellá, Jordi Guardiola, Mario F. Fraga, Alberto Villanueva, Ramón Salazar, Francisco Rodriguez-Moranta, Javier de Oca, Sebastiano Biondo, Agustin F. Fernández, Antonio Berenguer-Llergo, Daniel Azuara, and F. Javier Carmona more...
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PDF File - 916K, Representative pyrograms in a healthy colonic mucosa sample for the markers analyzed.
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- 2023
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5. Supplementary Methods from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
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Victor Moreno, Manel Esteller, Gabriel Capellá, Jordi Guardiola, Mario F. Fraga, Alberto Villanueva, Ramón Salazar, Francisco Rodriguez-Moranta, Javier de Oca, Sebastiano Biondo, Agustin F. Fernández, Antonio Berenguer-Llergo, Daniel Azuara, and F. Javier Carmona more...
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PDF file - 574K, Microarray pre-processing.
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- 2023
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6. Supplemental Table 1 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas more...
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Supplemental Table 1. Detailed clinical data for PPGL samples.
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- 2023
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7. Data from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas more...
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Purpose: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers.Experimental Design: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic).Results: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1–2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity.Conclusions: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020–30. ©2015 AACR. more...
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- 2023
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8. Supplemental Table 2 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas more...
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Supplemental Table 2. Bisulfite pyrosequencing primer sequences.
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- 2023
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9. supplemental legend from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas more...
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supplemental legend
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- 2023
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10. Supplemental Figure 1 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas more...
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Supplemental Figure 1. PNMT gene methylation in PPGL.
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- 2023
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11. Supplementary Figures 1-5 from Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies
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Manel Esteller, Yasuhisa Shinomura, Kohzoh Imai, Hiroyuki Yamamoto, Alberto Villanueva, Esteban Ballestar, Santiago Ropero, Fernando Setién, Agustin F. Fernández, and Hiroaki Taniguchi
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Supplementary Figures 1-5 from Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies
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- 2023
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12. Supplementary Table 1 from Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies
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Manel Esteller, Yasuhisa Shinomura, Kohzoh Imai, Hiroyuki Yamamoto, Alberto Villanueva, Esteban Ballestar, Santiago Ropero, Fernando Setién, Agustin F. Fernández, and Hiroaki Taniguchi
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Supplementary Table 1 from Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies
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- 2023
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13. Epigenetic Study of Cohort of Monozygotic Twins With Hypertrophic Cardiomyopathy Due to MYBPC3 (Cardiac Myosin‐Binding Protein C)
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Alfonso Peñarroya, Rebeca Lorca, José Julián Rodríguez Reguero, Juan Gómez, Pablo Avanzas, Juan Ramon Tejedor, Agustín F. Fernandez, and Mario F. Fraga
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DNA methylation ,epigenetics ,HCM ,monozygotic twins ,MYBPC3 pathogenic variant ,phenotypic expressivity ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Hypertrophic cardiomyopathy is an autosomal dominant cardiac disease. The mechanisms that determine its variable expressivity are poorly understood. Epigenetics could play a crucial role in bridging the gap between genotype and phenotype by orchestrating the interplay between the environment and the genome regulation. In this study we aimed to establish a possible correlation between the peripheral blood DNA methylation patterns and left ventricular hypertrophy severity in patients with hypertrophic cardiomyopathy, evaluating the potential impact of lifestyle variables and providing a biological context to the observed changes. Methods and Results Methylation data were obtained from peripheral blood samples (Infinium MethylationEPIC BeadChip arrays). We employed multiple pair‐matched models to extract genomic positions whose methylation correlates with the degree of left ventricular hypertrophy in 3 monozygotic twin pairs carrying the same founder pathogenic variant (MYBPC3 p.Gly263Ter). This model enables the isolation of the environmental influence, beyond age, on DNA methylation changes by removing the genetic background. Our results revealed a more anxious personality among more severely affected individuals. We identified 56 differentially methylated positions that exhibited moderate, proportional changes in methylation associated with left ventricular hypertrophy. These differentially methylated positions were enriched in regions regulated by repressor histone marks and tended to cluster at genes involved in left ventricular hypertrophy development, such as HOXA5, TRPC3, UCN3, or PLSCR2, suggesting that changes in peripheral blood may reflect myocardial alterations. Conclusions We present a unique pair‐matched model, based on 3 monozygotic twin pairs carrying the same founder pathogenic variant and different phenotypes. This study provides further evidence of the pivotal role of epigenetics in hypertrophic cardiomyopathy variable expressivity. more...
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- 2024
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14. A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment
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Raúl F. Pérez, Patricia Tezanos, Alfonso Peñarroya, Alejandro González-Ramón, Rocío G. Urdinguio, Javier Gancedo-Verdejo, Juan Ramón Tejedor, Pablo Santamarina-Ojeda, Juan José Alba-Linares, Lidia Sainz-Ledo, Annalisa Roberti, Virginia López, Cristina Mangas, María Moro, Elisa Cintado Reyes, Pablo Muela Martínez, Mar Rodríguez-Santamaría, Ignacio Ortea, Ramón Iglesias-Rey, Juan Castilla-Silgado, Cristina Tomás-Zapico, Eduardo Iglesias-Gutiérrez, Benjamín Fernández-García, Jose Vicente Sanchez-Mut, José Luis Trejo, Agustín F. Fernández, and Mario F. Fraga more...
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Science - Abstract
Abstract Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline. more...
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- 2024
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15. Novel 14q32.2 paternal deletion encompassing the whole DLK1 gene associated with Temple syndrome
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Neus Baena, David Monk, Cinthia Aguilera, Mario F. Fraga, Agustín F. Fernández, Elisabeth Gabau, Raquel Corripio, Nuria Capdevila, Juan Pablo Trujillo, Anna Ruiz, and Miriam Guitart
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Temple syndrome (TS14) ,Methylation ,DLK1 ,Deletion ,DMR ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty. Methods An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR. Results The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission. Conclusion We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR. more...
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- 2024
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16. Multi‐omic integration of DNA methylation and gene expression data reveals molecular vulnerabilities in glioblastoma
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Pablo Santamarina‐Ojeda, Juan Ramón Tejedor, Raúl F. Pérez, Virginia López, Annalisa Roberti, Cristina Mangas, Agustín F. Fernández, and Mario F. Fraga
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DNA methylation ,gene expression ,glioblastoma ,mesenchymal ,multi‐omics ,patient‐derived GBM stem cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Glioblastoma (GBM) is one of the most aggressive types of cancer and exhibits profound genetic and epigenetic heterogeneity, making the development of an effective treatment a major challenge. The recent incorporation of molecular features into the diagnosis of patients with GBM has led to an improved categorization into various tumour subtypes with different prognoses and disease management. In this work, we have exploited the benefits of genome‐wide multi‐omic approaches to identify potential molecular vulnerabilities existing in patients with GBM. Integration of gene expression and DNA methylation data from both bulk GBM and patient‐derived GBM stem cell lines has revealed the presence of major sources of GBM variability, pinpointing subtype‐specific tumour vulnerabilities amenable to pharmacological interventions. In this sense, inhibition of the AP‐1, SMAD3 and RUNX1/RUNX2 pathways, in combination or not with the chemotherapeutic agent temozolomide, led to the subtype‐specific impairment of tumour growth, particularly in the context of the aggressive, mesenchymal‐like subtype. These results emphasize the involvement of these molecular pathways in the development of GBM and have potential implications for the development of personalized therapeutic approaches. more...
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- 2023
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17. CRISPR/dCAS9-mediated DNA demethylation screen identifies functional epigenetic determinants of colorectal cancer
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Juan Ramón Tejedor, Alfonso Peñarroya, Javier Gancedo-Verdejo, Pablo Santamarina-Ojeda, Raúl F. Pérez, Sara López-Tamargo, Ana Díez-Borge, Juan J. Alba-Linares, Nerea González-del-Rey, Rocío G. Urdinguio, Cristina Mangas, Annalisa Roberti, Virginia López, Teresa Morales-Ruiz, Rafael R. Ariza, Teresa Roldán-Arjona, Mónica Meijón, Luis Valledor, María Jesús Cañal, Daniel Fernández-Martínez, María Fernández-Hevia, Paula Jiménez-Fonseca, Luis J. García-Flórez, Agustín F. Fernández, and Mario F. Fraga more...
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DNA methylation ,Gene expression ,Epigenetics ,Tumour suppressor gene ,CRISPR screen ,Colorectal cancer ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated. Results In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53−/− cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence. Conclusions These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes. more...
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- 2023
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18. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcomaResearch in context
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Verónica Rey, Juan Tornín, Juan Jose Alba-Linares, Cristina Robledo, Dzohara Murillo, Aida Rodríguez, Borja Gallego, Carmen Huergo, Cristina Viera, Alejandro Braña, Aurora Astudillo, Dominique Heymann, Karoly Szuhai, Judith V.M.G. Bovée, Agustín F. Fernández, Mario F. Fraga, Javier Alonso, and René Rodríguez more...
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Chondrosarcoma ,Enasidenib ,IDH2 ,Patient-derived models ,Personalized medicine ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. Methods: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). Findings: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. Interpretation: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. Funding: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027). more...
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- 2024
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19. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis
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Annalisa Roberti, Juan Ramon Tejedor, Irene Díaz-Moreno, Virginia López, Pablo Santamarina-Ojeda, Raúl F. Pérez, Rocío G. Urdinguio, Carmen Concellón, María Luz Martínez-Chantar, Juan Luis Fernández-Morera, Antonio Díaz-Quintana, Vicente del Amo, Agustín F. Fernández, and Mario F. Fraga more...
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Medicine ,Science - Abstract
Abstract Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity. more...
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- 2023
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20. A complex interplay between H2A.Z and HP1 isoforms regulates pericentric heterochromatin
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Jessica González, Laia Bosch-Presegué, Anna Marazuela-Duque, Anna Guitart-Solanes, María Espinosa-Alcantud, Agustín F. Fernandez, Jeremy P. Brown, Juan Ausió, Berta N. Vazquez, Prim B. Singh, Mario F. Fraga, and Alejandro Vaquero more...
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HP1α,β,γ ,heterochromatin ,H2A.Z ,epigenetics ,genome stability ,H3K9me3 ,Biology (General) ,QH301-705.5 - Abstract
Pericentric heterochromatin (PCH) plays an essential role in the maintenance of genome integrity and alterations in PCH have been linked to cancer and aging. HP1 α, β, and γ, are hallmarks of constitutive heterochromatin that are thought to promote PCH structure through binding to heterochromatin-specific histone modifications and interaction with a wide range of factors. Among the less understood components of PCH is the histone H2A variant H2A.Z, whose role in the organization and maintenance of PCH is poorly defined. Here we show that there is a complex interplay between H2A.Z and HP1 isoforms in PCH. While the loss of HP1α results in the accumulation of H2A.Z.1 in PCH, which is associated with a significant decrease in its mobile fraction, H2A.Z.1 binds preferentially to HP1β in these regions. Of note, H2A.Z.1 downregulation results in increased heterochromatinization and instability of PCH, reflected by accumulation of the major epigenetic hallmarks of heterochromatin in these regions and increased frequency of chromosome aberrations related to centromeric/pericentromeric defects. Our studies support a role for H2A.Z in genome stability and unveil a key role of H2A.Z in the regulation of heterochromatin-specific epigenetic modifications through a complex interplay with the HP1 isoforms. more...
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- 2023
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21. Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways
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Juan José Alba-Linares, Raúl F. Pérez, Juan Ramón Tejedor, David Bastante-Rodríguez, Francisco Ponce, Nuria García Carbonell, Rafael Gómez Zafra, Agustín F. Fernández, Mario F. Fraga, and Empar Lurbe
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Metabolism ,DNA methylation ,Epigenetics ,Obesity ,Gestational diabetes ,Newborn ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Obesity is a negative chronic metabolic health condition that represents an additional risk for the development of multiple pathologies. Epidemiological studies have shown how maternal obesity or gestational diabetes mellitus during pregnancy constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring. Furthermore, epigenetic remodelling may help explain the molecular mechanisms that underlie these epidemiological findings. Thus, in this study we explored the DNA methylation landscape of children born to mothers with obesity and gestational diabetes during their first year of life. Methods We used Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 genome-wide CpG sites in blood samples from a paediatric longitudinal cohort consisting of 26 children born to mothers who suffered from obesity or obesity with gestational diabetes mellitus during pregnancy and 13 healthy controls (measurements taken at 0, 6 and 12 month; total N = 90). We carried out cross-sectional and longitudinal analyses to derive DNA methylation alterations associated with developmental and pathology-related epigenomics. Results We identified abundant DNA methylation changes during child development from birth to 6 months and, to a lesser extent, up to 12 months of age. Using cross-sectional analyses, we discovered DNA methylation biomarkers maintained across the first year of life that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes. Importantly, enrichment analyses suggested that these alterations constitute epigenetic signatures that affect genes and pathways involved in the metabolism of fatty acids, postnatal developmental processes and mitochondrial bioenergetics, such as CPT1B, SLC38A4, SLC35F3 and FN3K. Finally, we observed evidence of an interaction between developmental DNA methylation changes and maternal metabolic condition alterations. Conclusions Our observations highlight the first six months of development as being the most crucial for epigenetic remodelling. Furthermore, our results support the existence of systemic intrauterine foetal programming linked to obesity and gestational diabetes that affects the childhood methylome beyond birth, which involves alterations related to metabolic pathways, and which may interact with ordinary postnatal development programmes. more...
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- 2023
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22. The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma
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Lucia Morgado-Palacin, Jessie A. Brown, Thomas F. Martinez, Juana M. Garcia-Pedrero, Farhad Forouhar, S. Aidan Quinn, Clara Reglero, Joan Vaughan, Yasamin Hajy Heydary, Cynthia Donaldson, Sandra Rodriguez-Perales, Eva Allonca, Rocio Granda-Diaz, Agustin F. Fernandez, Mario F. Fraga, Arianna L. Kim, Jorge Santos-Juanes, David M. Owens, Juan P. Rodrigo, Alan Saghatelian, and Adolfo A. Ferrando more...
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Science - Abstract
TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role. more...
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- 2023
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23. No genome-wide DNA methylation changes found associated with medium-term reduced graphene oxide exposure in human lung epithelial cells
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Raúl F. Pérez, Anna Yunuen Soto Fernández, Pablo Bousquets Muñoz, Marta I. Sierra, Juan Ramón Tejedor, Paula Morales-Sánchez, Adolfo F. Valdés, Ricardo Santamaría, Clara Blanco, Ramón Torrecillas, Mario F. Fraga, and Agustín F. Fernández more...
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epigenetics ,dna methylation ,nanomaterials ,graphene ,exposure ,Genetics ,QH426-470 - Abstract
The presence of nanomaterials in our everyday life is ever increasing, and so too are concerns about the possible health consequences of exposure to them. While evidence of their biological activity is growing, there is still scant knowledge of the epigenetic mechanisms that could be at play in these processes. Moreover, the great variability in the chemical and physical structures of these compounds handicaps the study of their possible health risks. Here we have synthesized reduced graphene oxide (rGO) through the thermal exfoliation/reduction of graphite oxide, and characterized the resulting material. We have then made use of Illumina’s MethylationEPIC arrays and bisulphite pyrosequencing to analyse the genome-wide and global DNA methylation dynamics associated with the medium-term exposure of human lung epithelial cells to rGO at concentrations of 1 and 10 µg/mL. The results show no genome-wide or global DNA methylation changes associated with either condition. Our observations thus suggest that medium-term rGO exposure does not have significant effects on the DNA methylation patterns of human lung epithelial cells. more...
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- 2020
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24. Physical exercise shapes the mouse brain epigenome
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Rocío G. Urdinguio, Juan Ramon Tejedor, Manuel Fernández-Sanjurjo, Raúl F. Pérez, Alfonso Peñarroya, Cecilia Ferrero, Helena Codina-Martínez, Carlos Díez-Planelles, Paola Pinto-Hernández, Juan Castilla-Silgado, Almudena Coto-Vilcapoma, Sergio Díez-Robles, Noelia Blanco-Agudín, Cristina Tomás-Zapico, Eduardo Iglesias-Gutiérrez, Benjamín Fernández-García, Agustin F. Fernandez, and Mario F. Fraga more...
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Epigenome ,Transcriptome ,Exercise ,Resistance training ,Endurance training ,Hippocampus ,Internal medicine ,RC31-1245 - Abstract
Objective: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice. Methods: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function. Results: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions. Conclusions: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research. more...
- Published
- 2021
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25. Epigenetic Deregulation of the Histone Methyltransferase KMT5B Contributes to Malignant Transformation in Glioblastoma
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Virginia López, Juan Ramón Tejedor, Antonella Carella, María G. García, Pablo Santamarina-Ojeda, Raúl F. Pérez, Cristina Mangas, Rocío G. Urdinguio, Aitziber Aranburu, Daniel de la Nava, María D. Corte-Torres, Aurora Astudillo, Manuela Mollejo, Bárbara Meléndez, Agustín F. Fernández, and Mario F. Fraga more...
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epigenetics ,glioblastoma ,histone methyltransferase ,histone posttranslational modification ,tumor suppressor ,Biology (General) ,QH301-705.5 - Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adulthood. Epigenetic mechanisms are known to play a key role in GBM although the involvement of histone methyltransferase KMT5B and its mark H4K20me2 has remained largely unexplored. The present study shows that DNA hypermethylation and loss of DNA hydroxymethylation is associated with KMT5B downregulation and genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Ectopic overexpression of KMT5B induced tumor suppressor-like features in vitro and in a mouse tumor xenograft model, as well as changes in the expression of several glioblastoma-related genes. H4K20me2 enrichment was found immediately upstream of the promoter regions of a subset of deregulated genes, thus suggesting a possible role for KMT5B in GBM through the epigenetic modulation of key target cancer genes. more...
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- 2021
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26. Epigenetics in cancer therapy and nanomedicine
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Annalisa Roberti, Adolfo F. Valdes, Ramón Torrecillas, Mario F. Fraga, and Agustin F. Fernandez
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Epigenetics ,DNMT inhibitors ,HDCA inhibitors ,Nanomedicine ,Nanoparticles ,Nanocarriers ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract The emergence of nanotechnology applied to medicine has revolutionized the treatment of human cancer. As in the case of classic drugs for the treatment of cancer, epigenetic drugs have evolved in terms of their specificity and efficiency, especially because of the possibility of using more effective transport and delivery systems. The use of nanoparticles (NPs) in oncology management offers promising advantages in terms of the efficacy of cancer treatments, but it is still unclear how these NPs may be affecting the epigenome such that safe routine use is ensured. In this work, we summarize the importance of the epigenetic alterations identified in human cancer, which have led to the appearance of biomarkers or epigenetic drugs in precision medicine, and we describe the transport and release systems of the epigenetic drugs that have been developed to date. more...
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- 2019
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27. Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation
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Annalisa Roberti, Agustín F. Fernández, and Mario F. Fraga
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Nicotinamide N-methyltransferase ,Epigenetics ,Metabolism ,Obesity ,Cancer ,Internal medicine ,RC31-1245 - Abstract
Background: The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD+) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated. Scope of review: This review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use. Major conclusions: NNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer. more...
- Published
- 2021
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28. Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes
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Raúl F. Pérez, Pablo Santamarina, Juan Ramón Tejedor, Rocío G. Urdinguio, Julio Álvarez-Pitti, Pau Redon, Agustín F. Fernández, Mario F. Fraga, and Empar Lurbe
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Epigenetics ,DNA methylation ,Histone modification ,Aging ,Newborn ,Longitudinal ,Medicine - Abstract
Abstract Background Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies. Methods To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects. Results We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements. Conclusions These data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life. more...
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- 2019
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29. Generation and characterization of a human iPSC cell line expressing inducible Cas9 in the 'safe harbor' AAVS1 locus
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Julio Castaño, Clara Bueno, Senda Jiménez-Delgado, Heleia Roca-Ho, Mario F. Fraga, Agustín F. Fernandez, Mahito Nakanishi, Raúl Torres-Ruiz, Sandra Rodríguez-Perales, and Pablo Menéndez
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Biology (General) ,QH301-705.5 - Abstract
We report the generation-characterization of a fetal liver (FL) B-cell progenitor (BCP)-derived human induced pluripotent stem cell (hiPSC) line CRISPR/Cas9-edited to carry/express a single copy of doxycycline-inducible Cas9 gene in the “safe locus” AAVS1 (iCas9-FL-BCP-hiPSC). Gene-edited iPSCs remained pluripotent after CRISPR/Cas9 genome-edition. Correct genomic integration of a unique copy of Cas9 was confirmed by PCR and Southern blot. Cas9 was robustly and specifically expressed on doxycycline exposure. T7-endonuclease assay demonstrated that iCas9 induces robust gene-edition when gRNAs against hematopoietic transcription factors were tested. This iCas9-FL-BCP-hiPSC will facilitate gene-editing approaches for studies on developmental biology, drug screening and disease modeling. more...
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- 2017
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30. Differential analysis of genome-wide methylation and gene expression in mesenchymal stem cells of patients with fractures and osteoarthritis
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Alvaro del Real, Flor M. Pérez-Campo, Agustín F. Fernández, Carolina Sañudo, Carmen G. Ibarbia, María I. Pérez-Núñez, Wim Van Criekinge, Maarten Braspenning, María A. Alonso, Mario F. Fraga, and Jose A. Riancho more...
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epigenetics ,osteoarthritis ,osteoporosis ,stem cells ,transcription factors ,Genetics ,QH426-470 - Abstract
Insufficient activity of the bone-forming osteoblasts leads to low bone mass and predisposes to fragility fractures. The functional capacity of human mesenchymal stem cells (hMSCs), the precursors of osteoblasts, may be compromised in elderly individuals, in relation with the epigenetic changes associated with aging. However, the role of hMSCs in the pathogenesis of osteoporosis is still unclear. Therefore, we aimed to characterize the genome-wide methylation and gene expression signatures and the differentiation capacity of hMSCs from patients with hip fractures. We obtained hMSCs from the femoral heads of women undergoing hip replacement due to hip fractures and controls with hip osteoarthritis. DNA methylation was explored with the Infinium 450K bead array. Transcriptome analysis was done by RNA sequencing. The genomic analyses revealed that most differentially methylated loci were situated in genomic regions with enhancer activity, distant from gene bodies and promoters. These regions were associated with differentially expressed genes enriched in pathways related to hMSC growth and osteoblast differentiation. hMSCs from patients with fractures showed enhanced proliferation and upregulation of the osteogenic drivers RUNX2/OSX. Also, they showed some signs of accelerated methylation aging. When cultured in osteogenic medium, hMSCs from patients with fractures showed an impaired differentiation capacity, with reduced alkaline phosphatase activity and poor accumulation of a mineralized matrix. Our results point to 2 areas of potential interest for discovering new therapeutic targets for low bone mass disorders and bone regeneration: the mechanisms stimulating MSCs proliferation after fracture and those impairing their terminal differentiation. more...
- Published
- 2017
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31. Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency
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Alvaro Muñoz-López, Damià Romero-Moya, Cristina Prieto, Verónica Ramos-Mejía, Antonio Agraz-Doblas, Ignacio Varela, Marcus Buschbeck, Anna Palau, Xonia Carvajal-Vergara, Alessandra Giorgetti, Anthony Ford, Majlinda Lako, Isabel Granada, Neus Ruiz-Xivillé, Sandra Rodríguez-Perales, Raul Torres-Ruíz, Ronald W. Stam, Jose Luis Fuster, Mario F. Fraga, Mahito Nakanishi, Gianni Cazzaniga, Michela Bardini, Isabel Cobo, Gustavo F. Bayon, Agustin F. Fernandez, Clara Bueno, and Pablo Menendez more...
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iPSC ,cancer reprogramming ,MLL-AF4 ,B-ALL ,Sendai virus ,transcriptome ,DNA methylome ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming “boosters” also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency. more...
- Published
- 2016
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32. Oncometabolic Nuclear Reprogramming of Cancer Stemness
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Javier A. Menendez, Bruna Corominas-Faja, Elisabet Cuyàs, María G. García, Salvador Fernández-Arroyo, Agustín F. Fernández, Jorge Joven, Mario F. Fraga, and Tomás Alarcón
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Oncometabolites ,reprogramming ,stemness ,cancer ,stem cells ,cancer stem cells ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells. more...
- Published
- 2016
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33. Correction: DNA Methylation Dynamics in Blood after Hematopoietic Cell Transplant.
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Ramon M. Rodriguez, Beatriz Suarez-Alvarez, Rubén Salvanés, Manuel Muro, Pablo Martínez-Camblor, Enrique Colado, Miguel Alcoceba Sánchez, Marcos González Díaz, Agustin F. Fernandez, Mario F. Fraga, and Carlos Lopez-Larrea more...
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Medicine ,Science - Published
- 2013
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