MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure
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. Met...
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Elsevier
2020-01-01
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Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419307819 |
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record_format |
Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Helena M. Pereira Alisson C. Cardoso Silvio R. Consonni Renata R. Oliveira Angela Saito Maria Luisa B. Vaggione Jose R. Matos-Souza Marcelo F. Carazzolle Anderson Gonçalves Juliano L. Fernandes Gustavo C.A. Ribeiro Mauricio M. Lopes Jeffery D. Molkentin Kleber G. Franchini |
spellingShingle |
Ana Helena M. Pereira Alisson C. Cardoso Silvio R. Consonni Renata R. Oliveira Angela Saito Maria Luisa B. Vaggione Jose R. Matos-Souza Marcelo F. Carazzolle Anderson Gonçalves Juliano L. Fernandes Gustavo C.A. Ribeiro Mauricio M. Lopes Jeffery D. Molkentin Kleber G. Franchini MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure EBioMedicine |
author_facet |
Ana Helena M. Pereira Alisson C. Cardoso Silvio R. Consonni Renata R. Oliveira Angela Saito Maria Luisa B. Vaggione Jose R. Matos-Souza Marcelo F. Carazzolle Anderson Gonçalves Juliano L. Fernandes Gustavo C.A. Ribeiro Mauricio M. Lopes Jeffery D. Molkentin Kleber G. Franchini |
author_sort |
Ana Helena M. Pereira |
title |
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
title_short |
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
title_full |
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
title_fullStr |
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
title_full_unstemmed |
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
title_sort |
mef2c repressor variant deregulation leads to cell cycle re-entry and development of heart failure |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2020-01-01 |
description |
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). Keywords: MEF2, Splicing, Heart failure, Dedifferentiation, Cell cycle re-entry, Cardiomyocyte, Sarcomere disassembly |
url |
http://www.sciencedirect.com/science/article/pii/S2352396419307819 |
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1725617634224898048 |
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doaj-ae13780517d24f1099e6a2e90f0cbaa02020-11-24T23:07:41ZengElsevierEBioMedicine2352-39642020-01-0151MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failureAna Helena M. Pereira0Alisson C. Cardoso1Silvio R. Consonni2Renata R. Oliveira3Angela Saito4Maria Luisa B. Vaggione5Jose R. Matos-Souza6Marcelo F. Carazzolle7Anderson Gonçalves8Juliano L. Fernandes9Gustavo C.A. Ribeiro10Mauricio M. Lopes11Jeffery D. Molkentin12Kleber G. Franchini13Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilDepartment of Biochemistry and Tissue Biology, University of Campinas, Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilDepartment of Internal Medicine, University of Campinas, Campinas, BrazilGenomics and Expression Laboratory, University of Campinas, Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, BrazilJose Michel Kalaf Research Institute, Campinas, BrazilCardiovascular Surgery, Pontifical Catholic University, Campinas, BrazilCardiology, Pontifical Catholic University, Campinas, BrazilCincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USABrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil; Department of Internal Medicine, University of Campinas, Campinas, Brazil; Corresponding author at: Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil.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). Keywords: MEF2, Splicing, Heart failure, Dedifferentiation, Cell cycle re-entry, Cardiomyocyte, Sarcomere disassemblyhttp://www.sciencedirect.com/science/article/pii/S2352396419307819 |