17 results on '"Ezequiel Petrillo"'
Search Results
2. Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer
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Santiago Madera, Franco Izzo, María F. Chervo, Agustina Dupont, Violeta A. Chiauzzi, Sofia Bruni, Ezequiel Petrillo, Sharon S. Merin, Mara De Martino, Diego Montero, Claudio Levit, Gabriel Lebersztein, Fabiana Anfuso, Agustina Roldán Deamicis, María F. Mercogliano, Cecilia J. Proietti, Roxana Schillaci, Patricia V. Elizalde, and Rosalía I. Cordo Russo
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Cytology ,QH573-671 - Abstract
Abstract Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.
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- 2022
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3. DeepSARS: simultaneous diagnostic detection and genomic surveillance of SARS-CoV-2
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Alexander Yermanos, Kai-Lin Hong, Andreas Agrafiotis, Jiami Han, Sarah Nadeau, Cecilia Valenzuela, Asli Azizoglu, Roy Ehling, Beichen Gao, Michael Spahr, Daniel Neumeier, Ching-Hsiang Chang, Andreas Dounas, Ezequiel Petrillo, Ina Nissen, Elodie Burcklen, Mirjam Feldkamp, Christian Beisel, Annette Oxenius, Miodrag Savic, Tanja Stadler, Fabian Rudolf, and Sai T. Reddy
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The continued spread of SARS-CoV-2 and emergence of new variants with higher transmission rates and/or partial resistance to vaccines has further highlighted the need for large-scale testing and genomic surveillance. However, current diagnostic testing (e.g., PCR) and genomic surveillance methods (e.g., whole genome sequencing) are performed separately, thus limiting the detection and tracing of SARS-CoV-2 and emerging variants. Results Here, we developed DeepSARS, a high-throughput platform for simultaneous diagnostic detection and genomic surveillance of SARS-CoV-2 by the integration of molecular barcoding, targeted deep sequencing, and computational phylogenetics. DeepSARS enables highly sensitive viral detection, while also capturing genomic diversity and viral evolution. We show that DeepSARS can be rapidly adapted for identification of emerging variants, such as alpha, beta, gamma, and delta strains, and profile mutational changes at the population level. Conclusions DeepSARS sets the foundation for quantitative diagnostics that capture viral evolution and diversity. Graphical abstract DeepSARS uses molecular barcodes (BCs) and multiplexed targeted deep sequencing (NGS) to enable simultaneous diagnostic detection and genomic surveillance of SARS-CoV-2. Image was created using Biorender.com .
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- 2022
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4. Apoplastic class III peroxidases PRX62 and PRX69 promote Arabidopsis root hair growth at low temperature
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Javier Martínez Pacheco, Philippe Ranocha, Luciana Kasulin, Corina M. Fusari, Lucas Servi, Ariel. A. Aptekmann, Victoria Berdion Gabarain, Juan Manuel Peralta, Cecilia Borassi, Eliana Marzol, Diana Rosa Rodríguez-Garcia, Yossmayer del Carmen Rondón Guerrero, Mariana Carignani Sardoy, Lucía Ferrero, Javier F. Botto, Claudio Meneses, Federico Ariel, Alejandro D. Nadra, Ezequiel Petrillo, Christophe Dunand, and José M. Estevez
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Science - Abstract
Arabidopsis root hair growth is enhanced at low temperatures. Here the authors show that the class III peroxidases PRX62 and PRX69 modulate ROS homeostasis and cell wall characteristics, and promote root hair elongation at low temperature.
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- 2022
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5. Editorial: Regulation of alternative splicing in plant stress responses
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Kranthi K. Mandadi, Ezequiel Petrillo, Alexandra S. Dubrovina, and Konstantin V. Kiselev
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alternative splicing ,post-transcriptional regulation ,plant growth and development ,abiotic stress ,biotic stress ,Plant culture ,SB1-1110 - Published
- 2023
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6. Editorial: Alternative Splicing Regulation in Plants
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Ezequiel Petrillo, Maria Kalyna, Kranthi K. Mandadi, Shih-Long Tu, and Craig G. Simpson
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splicing factor ,development ,stress ,adaptation ,evolution ,environment ,Plant culture ,SB1-1110 - Published
- 2020
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7. Alternative Splicing Regulation During Light-Induced Germination of Arabidopsis thaliana Seeds
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Rocío Soledad Tognacca, Lucas Servi, Carlos Esteban Hernando, Maite Saura-Sanchez, Marcelo Javier Yanovsky, Ezequiel Petrillo, and Javier Francisco Botto
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dormancy ,germination ,light ,phytochrome B (phyB) ,alternative splicing (AS) ,Arabidopsis ,Plant culture ,SB1-1110 - Abstract
Seed dormancy and germination are relevant processes for a successful seedling establishment in the field. Light is one of the most important environmental factors involved in the relief of dormancy to promote seed germination. In Arabidopsis thaliana seeds, phytochrome photoreceptors tightly regulate gene expression at different levels. The contribution of alternative splicing (AS) regulation in the photocontrol of seed germination is still unknown. The aim of this work is to study gene expression modulated by light during germination of A. thaliana seeds, with focus on AS changes. Hence, we evaluated transcriptome-wide changes in stratified seeds irradiated with a pulse of red (Rp) or far-red (FRp) by RNA sequencing (RNA-seq). Our results show that the Rp changes the expression of ∼20% of the transcriptome and modifies the AS pattern of 226 genes associated with mRNA processing, RNA splicing, and mRNA metabolic processes. We further confirmed these effects for some of the affected AS events. Interestingly, the reverse transcriptase–polymerase chain reaction (RT–PCR) analyses show that the Rp modulates the AS of splicing-related factors (At-SR30, At-RS31a, At-RS31, and At-U2AF65A), a light-signaling component (At-PIF6), and a dormancy-related gene (At-DRM1). Furthermore, while the phytochrome B (phyB) is responsible for the AS pattern changes of At-U2AF65A and At-PIF6, the regulation of the other AS events is independent of this photoreceptor. We conclude that (i) Rp triggers AS changes in some splicing factors, light-signaling components, and dormancy/germination regulators; (ii) phyB modulates only some of these AS events; and (iii) AS events are regulated by R and FR light, but this regulation is not directly associated with the intensity of germination response. These data will help in boosting research in the splicing field and our understanding about the role of this mechanism during the photocontrol of seed germination.
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- 2019
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8. New Era in Plant Alternative Splicing Analysis Enabled by Advances in High-Throughput Sequencing (HTS) Technologies
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Renesh Bedre, Sonia Irigoyen, Ezequiel Petrillo, and Kranthi K. Mandadi
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alternative splicing ,high-throughput sequencing ,bioinformatics ,RNA-seq ,PCR ,non-sense-mediated decay ,Plant culture ,SB1-1110 - Published
- 2019
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9. Nuclear ErbB-2-Induced Transcriptome Drives Triple Negative Breast Cancer Growth
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Nicolás Bellora, Tim H-M Huang, Agustina Roldán Deamicis, Rosalia Ines Cordo Russo, Patricia V. Elizalde, María F. Chervo, Santiago Madera, Micaela Parra, Cecilia J. Proietti, Kohzoh Mitsuya, Violeta A. Chiauzzi, Ezequiel Petrillo, and Roxana Schillaci
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Transcriptome ,Text mining ,ErbB ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cancer research ,Tumor Biology ,Biology ,business ,Triple-negative breast cancer ,Hormone Actions in Tumor Biology: From New Mechanisms to Therapy ,AcademicSubjects/MED00250 - Abstract
Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2 tyrosine kinase receptor. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Gene expression analyses have categorized TNBC into distinct molecular subtypes. Up to 78% of clinical TNBCs belong to the basal-like (BL) subtype. Here we found ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing, using a PCR-sequencing approach combined with RNA interference, revealed that BL TNBC cells express the canonical ErbB-2 (WTErbB-2), encoded by transcript 1, and the non-canonical isoform c, encoded by alternative transcript 3 (T3). The latter was not previously reported in normal or malignant cells. To characterize the isoform c we designed siRNAs targeting T3 (T3 siRNAs), which silenced up to 93% of said isoform. Transfection of T3 siRNAs into BL cells expressing only isoform c or both isoform c and WTErbB-2 was sufficient to decrease cell proliferation. Intratumoral injections of T3 siRNAs into mice bearing BL TN tumors also blocked in vivo growth. To explore whether isoform c growth-promoting effect is due to its functions as a transcriptional regulator, we performed RNA-seq in BL cells expressing only this isoform. We identified a set of genes differentially regulated in BL cells where we evicted isoform c from the nucleus, as compared to control cells. In the up-regulated group, we found enrichment of pro-apoptotic and tumor suppressor genes and in the down-regulated one, genes involved in proliferation and stemness. We used gene set enrichment analysis (GSEA) to identify the biological processes associated with these isoform c-regulated genes. We found a pronounced enrichment of gene sets related to apoptosis, activation of DNA damage pathways and cell cycle arrest in response to eviction of nuclear isoform c. GSEA also revealed negative regulation of gene sets involved in cell motility, cellular differentiation and growth pathways in BL cells lacking nuclear isoform c expression. These results suggest that NErbB-2 function modulates tumor growth and promotes a metastatic phenotype in TNBC. Furthermore, our clinical findings identified NErbB-2 as an independent predictor of shorter OS (HR 2.54; 95% CI 1.22-5.28; P = 0.013), DFS (HR 2.91; 95% CI 1.44-5.87; P = 0.003), and DMFS (HR 2.59; 95% CI 1.20-5.60; P = 0.015) in 99 TN primary tumors. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type proteins, which conserve the canonical domains and are located in their classical cellular compartments, highlighting the potential of NErbB-2 isoforms as novel therapeutic targets and clinical biomarkers in TNBC.
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- 2021
10. Alternative Splicing Regulation During Light-Induced Germination of Arabidopsis thaliana Seeds
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Marcelo J. Yanovsky, Carlos Esteban Hernando, Maite Saura-Sanchez, Lucas Servi, Ezequiel Petrillo, Javier Francisco Botto, and Rocío Soledad Tognacca
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0106 biological sciences ,0301 basic medicine ,dormancy ,alternative splicing (AS) ,Arabidopsis ,Plant Science ,lcsh:Plant culture ,01 natural sciences ,purl.org/becyt/ford/1 [https] ,Ciencias Biológicas ,03 medical and health sciences ,Gene expression ,lcsh:SB1-1110 ,purl.org/becyt/ford/1.6 [https] ,biology ,Phytochrome ,DORMANCY ,Alternative splicing ,Seed dormancy ,phytochrome B (phyB) ,Bioquímica y Biología Molecular ,biology.organism_classification ,ARABIDOPSIS ,Cell biology ,030104 developmental biology ,LIGHT ,germination ,Germination ,RNA splicing ,Dormancy ,ALTERNATIVE SPLICING (AS) ,light ,PHYTOCHROME B (PHYB) ,CIENCIAS NATURALES Y EXACTAS ,010606 plant biology & botany ,GERMINATION - Abstract
Seed dormancy and germination are relevant processes for a successful seedling establishment in the field. Light is one of the most important environmental factors involved in the relief of dormancy to promote seed germination. In Arabidopsis thaliana seeds, phytochrome photoreceptors tightly regulate gene expression at different levels. The contribution of alternative splicing (AS) regulation in the photocontrol of seed germination is still unknown. The aim of this work is to study gene expression modulated by light during germination of A. thaliana seeds, with focus on AS changes. Hence, we evaluated transcriptome-wide changes in stratified seeds irradiated with a pulse of red (Rp) or far-red (FRp) by RNA sequencing (RNA-seq). Our results show that the Rp changes the expression of ∼20% of the transcriptome and modifies the AS pattern of 226 genes associated with mRNA processing, RNA splicing, and mRNA metabolic processes. We further confirmed these effects for some of the affected AS events. Interestingly, the reverse transcriptase–polymerase chain reaction (RT–PCR) analyses show that the Rp modulates the AS of splicing-related factors (At-SR30, At-RS31a, At-RS31, and At-U2AF65A), a light-signaling component (At-PIF6), and a dormancy-related gene (At-DRM1). Furthermore, while the phytochrome B (phyB) is responsible for the AS pattern changes of At-U2AF65A and At-PIF6, the regulation of the other AS events is independent of this photoreceptor. We conclude that (i) Rp triggers AS changes in some splicing factors, light-signaling components, and dormancy/germination regulators; (ii) phyB modulates only some of these AS events; and (iii) AS events are regulated by R and FR light, but this regulation is not directly associated with the intensity of germination response. These data will help in boosting research in the splicing field and our understanding about the role of this mechanism during the photocontrol of seed germination. Fil: Tognacca, Rocío Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Servi, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Hernando, Carlos Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Saura Sanchez, Maite. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina Fil: Yanovsky, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Botto, Javier Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina
- Published
- 2019
11. Light remote control of alternative splicing in roots through TOR kinase
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Lucas Servi, Alois Schweighofer, Peter Venhuizen, Craig G. Simpson, Armin Fuchs, Andrea Barta, Christian Meyer, John W. S. Brown, Maria Kalyna, Kubaczka Mg, Herz Mag, Ezequiel Petrillo, and Stefan Riegler
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0106 biological sciences ,0303 health sciences ,Kinase ,Alternative splicing ,Regulator ,Mitochondrion ,Biology ,01 natural sciences ,Cell biology ,Chloroplast ,03 medical and health sciences ,Gene expression ,Kinase activity ,Function (biology) ,030304 developmental biology ,010606 plant biology & botany - Abstract
SummaryFor plants, light is the source of energy and the most relevant regulator of growth and adaptations to the environment by inducing changes in gene expression at various levels, including alternative splicing. Chloroplasts trigger retrograde signals that control alternative splicing in leaves and roots in response to light. Here we provide evidence suggesting that sugars, derived from photosynthesis, act as mobile signals controlling alternative splicing in roots. The inhibition of TOR kinase activity diminishes the alternative splicing response to light and/or sugars in roots, showing the relevance of the TOR pathway in this signaling mechanism. Furthermore, disrupting the function of the mitochondria abolishes alternative splicing changes supporting a key role for these organelles in this signaling axis. We conclude that sugars can act as mobile signals coordinating alternative splicing responses to light throughout the whole plant, exerting this function in roots by activating the TOR pathway.Graphical AbstractArt by Dr. Luciana Giono.
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- 2018
- Full Text
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12. Let there be light: Regulation of gene expression in plants
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Alberto R. Kornblihtt, Andrea Barta, Maria Kalyna, Micaela A. Godoy Herz, and Ezequiel Petrillo
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retrograde signaling ,0106 biological sciences ,Light ,Arabidopsis ,Points-of-View ,Biology ,01 natural sciences ,Ciencias Biológicas ,purl.org/becyt/ford/1 [https] ,alternative splicing ,03 medical and health sciences ,chloroplast ,Gene Expression Regulation, Plant ,Transcription (biology) ,Gene expression ,ALTERNATIVE SPLICING ,Photosynthesis ,RETROGRADE SIGNALING ,purl.org/becyt/ford/1.6 [https] ,Molecular Biology ,Gene ,030304 developmental biology ,2. Zero hunger ,Genetics ,Regulation of gene expression ,0303 health sciences ,Messenger RNA ,PHOTORECEPTORS ,Arabidopsis Proteins ,Alternative splicing ,CHLOROPLAST ,RNA ,photoreceptors ,Cell Biology ,Bioquímica y Biología Molecular ,Cell biology ,LIGHT ,RNA splicing ,CIENCIAS NATURALES Y EXACTAS ,010606 plant biology & botany - Abstract
Gene expression regulation relies on a variety of molecular mechanisms affecting different steps of a messenger RNA (mRNA) life: transcription, processing, splicing, alternative splicing, transport, translation, storage and decay. Light induces massive reprogramming of gene expression in plants. Differences in alternative splicing patterns in response to environmental stimuli suggest that alternative splicing plays an important role in plant adaptation to changing life conditions. In a recent publication, our laboratories showed that light regulates alternative splicing of a subset of Arabidopsis genes encoding proteins involved in RNA processing by chloroplast retrograde signals. The light effect on alternative splicing is also observed in roots when the communication with the photosynthetic tissues is not interrupted, suggesting that a signaling molecule travels through the plant. These results point at alternative splicing regulation by retrograde signals as an important mechanism for plant adaptation to their environment. Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Medical University of Vienna; Austria Fil: Godoy Herz, Micaela Amalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina Fil: Barta, Andrea. Medical University of Vienna; Austria Fil: Kalyna, Maria. University of Natural Resources and Life Sciences; Austria Fil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina
- Published
- 2014
13. Shedding light on the chloroplast as a remote control of nuclear gene expression
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Alberto R. Kornblihtt, Andrea Barta, Maria Kalyna, Micaela A. Godoy Herz, and Ezequiel Petrillo
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0106 biological sciences ,Photoreceptors, Plant ,Phototropin ,Nuclear gene ,Chloroplasts ,Light Signal Transduction ,Light ,Otras Ciencias Biológicas ,Plant Science ,Biology ,Chloroplast ,01 natural sciences ,Ciencias Biológicas ,03 medical and health sciences ,alternative splicing ,retrograde signal ,Cryptochrome ,chloroplast ,Gene Expression Regulation, Plant ,030304 developmental biology ,Cell Nucleus ,0303 health sciences ,Phytochrome ,Alternative splicing ,Photoreceptor protein ,food and beverages ,Mini-Review ,Molecular biology ,Cell biology ,Retrograde signaling ,RNA ,sense organs ,Retrograde signal ,CIENCIAS NATURALES Y EXACTAS ,010606 plant biology & botany - Abstract
Plants rely on a sophisticated light sensing and signaling system that allows them to respond to environmental changes. Photosensory protein systems -phytochromes, cryptochromes, phototropins, and ultraviolet (UV)-B photoreceptors- have evolved to let plants monitor light conditions and regulate different levels of gene expression and developmental processes. However, even though photoreceptor proteins are best characterized and deeply studied, it is also known that chloroplasts are able to sense light conditions and communicate the variations to the nucleus that adjust its transcriptome to the changing environment. The redox state of components of the photosynthetic electron transport chain works as a sensor of photosynthetic activity and can affect nuclear gene expression by a retrograde signaling pathway. Recently, our groups showed that a retrograde signaling pathway can modulate the alternative splicing process, revealing a novel layer of gene expression control by chloroplast retrograde signaling. Fil: Godoy Herz, Micaela Amalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Barta, Andrea. Medical University of Vienna; Austria Fil: Kalyna, Maria. University of Natural Resources and Life Sciences; Austria Fil: Petrillo, Ezequiel. Medical University of Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
- Published
- 2014
14. Intragenic epigenetic changes modulate NCAM alternative splicing in neuronal differentiation
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Alberto R. Kornblihtt, Ignacio E. Schor, Ezequiel Petrillo, and Ana Fiszbein
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CHROMATIN ,Chromatin Immunoprecipitation ,Cellular differentiation ,Biology ,Real-Time Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Article ,Epigenesis, Genetic ,Ciencias Biológicas ,Exon ,Mice ,Cell Line, Tumor ,Animals ,ALTERNATIVE SPLICING ,Epigenetics ,RNA, Small Interfering ,Molecular Biology ,Neural Cell Adhesion Molecules ,DNA Primers ,Neurons ,General Immunology and Microbiology ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Alternative splicing ,Intron ,Cell Differentiation ,Azepines ,Exons ,Sequence Analysis, DNA ,Bioquímica y Biología Molecular ,respiratory system ,DNA Methylation ,Molecular biology ,Chromatin ,Alternative Splicing ,DIFFERENTIATION ,nervous system ,RNA splicing ,Azacitidine ,Quinazolines ,Neural cell adhesion molecule ,POL II ELONGATION ,CIENCIAS NATURALES Y EXACTAS - Abstract
Alternative splicing contributes to cell type-specific transcriptomes. Here, we show that changes in intragenic chromatin marks affect NCAM (neural cell adhesion molecule) exon 18 (E18) alternative splicing during neuronal differentiation. An increase in the repressive marks H3K9me2 and H3K27me3 along the gene body correlated with inhibition of polymerase II elongation in the E18 region, but without significantly affecting total mRNA levels. Treatment with the general DNA methylation inhibitor 5-azacytidine and BIX 01294, a specific inhibitor of H3K9 dimethylation, inhibited the differentiation-induced E18 inclusion, pointing to a role for repressive marks in sustaining NCAM splicing patterns typical of mature neurons. We demonstrate that intragenic deployment of repressive chromatin marks, induced by intronic small interfering RNAs targeting NCAM intron 18, promotes E18 inclusion in undifferentiated N2a cells, confirming the chromatin changes observed upon differentiation to be sufficient to induce alternative splicing. Combined with previous evidence that neuronal depolarization causes H3K9 acetylation and subsequent E18 skipping, our results show how two alternative epigenetic marks regulate NCAM alternative splicing and E18 levels in different cellular contexts. Fil: Schor, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Fiszbein, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
- Published
- 2013
15. Alternative splicing: a pivotal step between eukaryotic transcription and translation
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Mariano Alló, Gwendal Dujardin, Manuel J. Muñoz, Ezequiel Petrillo, Alberto R. Kornblihtt, and Ignacio E. Schor
- Subjects
Transcription, Genetic ,Computational biology ,Biology ,Ciencias Biológicas ,Transcription (biology) ,RNA Precursors ,Animals ,Humans ,Molecular Biology ,Transcription factor ,Gene ,Genetics ,Alternative splicing ,Eukaryotic transcription ,Eukaryota ,Cell Biology ,Bioquímica y Biología Molecular ,Chromatin ,Alternative Splicing ,Multicellular organism ,SPLICING ALTERNATIVO ,Protein Biosynthesis ,RNA splicing ,Spliceosomes ,SPLICING ,CIENCIAS NATURALES Y EXACTAS ,Signal Transduction ,Transcription Factors - Abstract
Alternative splicing was discovered simultaneously with splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of alternative splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places alternative splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the splicing machinery but also to transcription factors and chromatin structure. Fil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Schor, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Alló, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Dujardin, Gwendal. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Muñoz, Manuel Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
- Published
- 2013
16. Alternative splicing at the right time
- Author
-
Ezequiel Petrillo, Alberto R. Kornblihtt, Marcelo J. Yanovsky, and Sabrina E. Sanchez
- Subjects
Genetics ,Protein-Arginine N-Methyltransferases ,Models, Genetic ,Arabidopsis Proteins ,Protein arginine methyltransferase 5 ,Circadian clock ,Alternative splicing ,Arabidopsis ,Context (language use) ,Cell Biology ,Computational biology ,Biology ,Alternative Splicing ,Drosophila melanogaster ,Circadian Clocks ,RNA splicing ,Proteome ,Animals ,Drosophila Proteins ,Epigenetics ,Circadian rhythm ,Protein Methyltransferases ,Molecular Biology ,Point of View - Abstract
Alternative splicing (AS) allows the production of multiple mRNA variants from a single gene, which contributes to increase the complexity of the proteome. There is evidence that AS is regulated not only by auxiliary splicing factors, but also by components of the core spliceosomal machinery, as well as through epigenetic modifications. However, to what extent these different mechanisms contribute to the regulation of AS in response to endogenous or environmental stimuli is still unclear. Circadian clocks allow organisms to adjust physiological processes to daily changes in environmental conditions. Here we review recent evidence linking circadian clock and AS, and discuss the role of Protein Arginine Methyltransferase 5 (PRMT5) in these processes. We propose that the interactions between daily oscillations in AS and circadian rhythms in the expression of splicing factors and epigenetic regulators offer a great opportunity to dissect the contribution of these mechanisms to the regulation of AS in a physiologically relevant context.
- Published
- 2011
17. A methyl transferase links the circadian clock to the regulation of alternative splicing
- Author
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Esteban J. Beckwith, Craig G. Simpson, Fernanda M. Ceriani, Mathias L. Rugnone, Alberto R. Kornblihtt, Paloma Mas, C. Esteban Hernando, Micaela A. Godoy Herz, Sabrina E. Sanchez, Marcelo J. Yanovsky, Pablo D. Cerdán, Xu Zhang, Ana Depetris-Chauvin, Juan C. Cuevas, Justin O. Borevitz, Ezequiel Petrillo, John W. S. Brown, Yanovsky, Marcelo J., Fundación Antorchas, Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Universidad de Buenos Aires, European Commission, Howard Hughes Medical Institute, Ministerio de Educación y Ciencia (España), and EMBO
- Subjects
Protein-Arginine N-Methyltransferases ,Light ,Period (gene) ,Circadian clock ,Arabidopsis ,Biology ,Methylation ,RAR-related orphan receptor alpha ,Gene Expression Regulation, Plant ,Circadian Clocks ,RNA Precursors ,Animals ,Drosophila Proteins ,Protein Methyltransferases ,RNA, Messenger ,Circadian rhythm ,Hardware_REGISTER-TRANSFER-LEVELIMPLEMENTATION ,Genetics ,Multidisciplinary ,Base Sequence ,Arabidopsis Proteins ,Gene Expression Profiling ,ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS ,Alternative splicing ,Neurosciences ,Period Circadian Proteins ,Darkness ,Bacterial circadian rhythms ,Circadian Rhythm ,CLOCK ,ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS ,Alternative Splicing ,Drosophila melanogaster ,Phenotype ,Neurons and Cognition ,Mutation ,RNA splicing ,Spliceosomes ,RNA Splice Sites ,InformationSystems_MISCELLANEOUS ,Transcription Factors ,Autre (Sciences du Vivant) - Abstract
HAL Id: hal-01218274, Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day–night cycle. Post-transcriptional regulation is emerging as an important component of circadian networks, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones and Sm spliceosomal proteins, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5′-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions., This work was supported by grants from the Fundación Antorchas, the Agencia Nacional de Promoción de Ciencia y Tecnología of Argentina, the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina and the University of Buenos Aires to M.J.Y. and A.R.K., and from the European Union Network of Excellence on Alternative Splicing (EURASNET) to A.R.K. and J.W.S.B. M.J.Y. and A.R.K. are Howard Hughes Medical Institute international research scholars. P.M.’s laboratory is supported by a Ministerio de Educación y Ciencia grant, the European Young Investigator Awards and the EMBO Young Investigator Awards; M.F.C.’s laboratory is supported by Proyecto de Investigación Científica y Tecnológica 2006-1249.
- Published
- 2010
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