{"doi":"10.1016/j.ebiom.2019.11.032","title":"MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure","abstract":null,"journal":"EBioMedicine","year":2020,"id":677732,"datarank":0.4636563680037475,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.0,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":240332,"name":"Alisson C. Cardoso","orcid":"0000-0002-3051-9976","position":1,"is_corresponding":false},{"id":1132658,"name":"Sílvio Roberto Consonni","orcid":"0000-0003-3149-021X","position":2,"is_corresponding":false},{"id":1770794,"name":"Renata R. Oliveira","orcid":null,"position":3,"is_corresponding":false},{"id":1770795,"name":"Angela Saito","orcid":null,"position":4,"is_corresponding":false},{"id":1770796,"name":"Maria Luisa B. Vaggione","orcid":"0000-0002-9319-3475","position":5,"is_corresponding":false},{"id":1770797,"name":"Jose R. Matos-Souza","orcid":null,"position":6,"is_corresponding":false},{"id":1770800,"name":"Marcelo F. Carazzolle","orcid":null,"position":7,"is_corresponding":false},{"id":1770802,"name":"Anderson Gonçalves","orcid":"0000-0003-4510-4228","position":8,"is_corresponding":false},{"id":1770804,"name":"Juliano L. Fernandes","orcid":null,"position":9,"is_corresponding":false},{"id":1770806,"name":"Gustavo C.A. Ribeiro","orcid":null,"position":10,"is_corresponding":false},{"id":1770807,"name":"Mauricio M. Lopes","orcid":null,"position":11,"is_corresponding":false},{"id":289834,"name":"Jeffery D. Molkentin","orcid":"0000-0002-3558-6529","position":12,"is_corresponding":false},{"id":1770809,"name":"Kleber G. Franchini","orcid":null,"position":13,"is_corresponding":false},{"id":1770791,"name":"Ana Helena M. Pereira","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure","abstract":"BACKGROUND: A pathophysiological link exists between dysregulation of MEF2C transcription factors and heart failure (HF), but the underlying mechanisms remain elusive. Alternative splicing of MEF2C exons α, β and γ provides transcript diversity with gene activation or repression functionalities. METHODS: Neonatal and adult rat ventricular myocytes were used to overexpress MEF2C splicing variants γ+ (repressor) or γ-, or the inactive MEF2Cγ+23/24 (K23T/R24L). Phenotypic alterations in cardiomyocytes were determined by confocal and electron microscopy, flow cytometry and DNA microarray. We used transgenic mice with cardiac-specific overexpression of MEF2Cγ+ or MEF2Cγ- to explore the impact of MEF2C variants in cardiac phenotype. Samples of non-infarcted areas of the left ventricle from patients and mouse model of myocardial infarction were used to detect the expression of MEF2Cγ+ in failing hearts. FINDINGS: We demonstrate a previously unrealized upregulation of the transrepressor MEF2Cγ+ isoform in human and mouse failing hearts. We show that adenovirus-mediated overexpression of MEF2Cγ+ downregulates multiple MEF2-target genes, and drives incomplete cell-cycle reentry, partial dedifferentiation and apoptosis in the neonatal and adult rat. None of these changes was observed in cardiomyocytes overexpressing MEF2Cγ-. Transgenic mice overexpressing MEF2Cγ+, but not the MEF2Cγ-, developed dilated cardiomyopathy, correlated to cell-cycle reentry and apoptosis of cardiomyocytes. INTERPRETATION: Our results provide a mechanistic link between MEF2Cγ+ and deleterious abnormalities in cardiomyocytes, supporting the notion that splicing dysregulation in MEF2C towards the selection of the MEF2Cγ+ variant contributes to the pathogenesis of HF by promoting cardiomyocyte dropout. FUNDING: São Paulo Research Foundation (FAPESP); Brazilian National Research Council (CNPq).","is_dataset_classified":null,"base_score":3.091042453358316,"endowment":3.091042453358316,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31911274","pmcid":"PMC6948164","openalex_id":"https://openalex.org/W2997415033","authors":[],"funders":[{"funder_name":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","grant_id":"312203/2012-8","title":null},{"funder_name":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","grant_id":"310536/2014-6","title":null},{"funder_name":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","grant_id":"304366/2009-9","title":null},{"funder_name":"Fundação de Amparo à Pesquisa do Estado de São Paulo","grant_id":"2008/53583 - 5","title":null},{"funder_name":"Fundação de Amparo à Pesquisa do Estado de São Paulo","grant_id":"2008/53519 - 5","title":null},{"funder_name":"Laboratório Nacional de Biociências","grant_id":"","title":null},{"funder_name":"Centro Nacional de Pesquisa em Energia e Materiais","grant_id":"","title":null},{"funder_name":"Ludwig Boltzmann Institut für Experimentelle und Klinische Traumatologie","grant_id":"","title":null}],"total_grants":8,"fwci":1.0434,"citation_percentile":0.74257724,"influential_citations":0,"citation_trend":[{"year":2020,"count":2},{"year":2021,"count":3},{"year":2022,"count":5},{"year":2023,"count":4},{"year":2024,"count":3},{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1016/j.ebiom.2019.11.032","host_type":"journal"},{"url":"https://doi.org/10.1016/j.ebiom.2019.11.032","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S2352396419307819?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S2352396419307819?httpAccept=text/plain","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31911274","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6948164","host_type":"repository"},{"url":"https://doaj.org/article/ae13780517d24f1099e6a2e90f0cbaa0","host_type":"repository"},{"url":"http://www.thelancet.com/article/S2352396419307819/pdf","host_type":"Unpaywall"},{"url":"https://europepmc.org/articles/PMC6948164","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6948164?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Congenital heart defects research","Cardiac Fibrosis and Remodeling","Cardiomyopathy and Myosin Studies","Alternative Splicing","Animals","Apoptosis","Cell Cycle","Disease Models, Animal","Gene Expression Regulation","Genetic Association Studies","Genetic Predisposition to Disease","Genetic Variation","Heart Failure","Humans","MEF2 Transcription Factors","Mice","Mice, Transgenic","Myocytes, Cardiac","Rats"],"mesh_terms":["Animals","Cell Cycle","Disease Models, Animal","Gene Expression Regulation","Heart Failure","Humans","Mice, Transgenic","Genetic Variation","Apoptosis","Alternative Splicing","Genetic Predisposition to Disease","Myocytes, Cardiac","Mice","Rats","Genetic Association Studies","MEF2 Transcription Factors"],"keywords":["MEF2C","Biology","Mef2","Cell biology","Alternative splicing","Downregulation and upregulation","Cancer research","Transcription factor","Genetics","Gene","Gene isoform","Enhancer","Dedifferentiation","Cardiomyocyte","Splicing","Heart Failure","Cell Cycle Re-entry","Sarcomere Disassembly"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T04:28:27.289061Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}