Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy

Roberto Papait, Simone Serio, Christina Pagiatakis, Francesca Rusconi, Pierluigi Carullo, Marta Mazzola, Nicolò Salvarani, Michele Miragoli, Gianluigi Condorelli

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND: Correct gene expression programming of the cardiomyocyte underlies the normal functioning of the heart. Alterations to this can lead to the loss of cardiac homeostasis, triggering heart dysfunction. Although the role of some histone methyltransferases in establishing the transcriptional program of postnatal cardiomyocytes during heart development has been shown, the function of this class of epigenetic enzymes is largely unexplored in the adult heart. In this study, we investigated the role of G9a/Ehmt2, a histone methyltransferase that defines a repressive epigenetic signature, in defining the transcriptional program for cardiomyocyte homeostasis and cardiac hypertrophy. METHODS: We investigated the function of G9a in normal and stressed cardiomyocytes with the use of a conditional, cardiacspecific G9a knockout mouse, a specific G9a inhibitor, and highthroughput approaches for the study of the epigenome (chromatin immunoprecipitation sequencing) and transcriptome (RNA sequencing); traditional methods were used to assess cardiac function and cardiovascular disease. RESULTS: We found that G9a is required for cardiomyocyte homeostasis in the adult heart by mediating the repression of key genes regulating cardiomyocyte function via dimethylation of H3 lysine 9 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, and MEF2C-dependent gene expression by forming a complex with this transcription factor. The G9a-MEF2C complex was found to be required also for the maintenance of heterochromatin needed for the silencing of developmental genes in the adult heart. Moreover, G9a promoted cardiac hypertrophy by repressing antihypertrophic genes. CONCLUSIONS: Taken together, our findings demonstrate that G9a orchestrates critical epigenetic changes in cardiomyocytes in physiological and pathological conditions, thereby providing novel therapeutic avenues for cardiac pathologies associated with dysregulation of these mechanisms.

Original languageEnglish
Pages (from-to)1233-1246
Number of pages14
JournalCirculation
Volume136
Issue number13
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Cardiac Myocytes
Hypertrophy
Homeostasis
Epigenomics
Cardiomegaly
Polycomb Repressive Complex 2
RNA Sequence Analysis
Developmental Genes
Gene Expression
Heterochromatin
Chromatin Immunoprecipitation
histone methyltransferase
Transcriptome
Knockout Mice
Genes
Lysine
Heart Diseases
Catalytic Domain
Transcription Factors
Cardiovascular Diseases

Keywords

  • EHMT2 protein
  • Epigenomics
  • Heart failure
  • Heterochromatin
  • Histone methylation
  • Hypertrophy
  • MEF2C protein
  • Mouse

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy. / Papait, Roberto; Serio, Simone; Pagiatakis, Christina; Rusconi, Francesca; Carullo, Pierluigi; Mazzola, Marta; Salvarani, Nicolò; Miragoli, Michele; Condorelli, Gianluigi.

In: Circulation, Vol. 136, No. 13, 01.09.2017, p. 1233-1246.

Research output: Contribution to journalArticle

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AU - Papait, Roberto

AU - Serio, Simone

AU - Pagiatakis, Christina

AU - Rusconi, Francesca

AU - Carullo, Pierluigi

AU - Mazzola, Marta

AU - Salvarani, Nicolò

AU - Miragoli, Michele

AU - Condorelli, Gianluigi

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N2 - BACKGROUND: Correct gene expression programming of the cardiomyocyte underlies the normal functioning of the heart. Alterations to this can lead to the loss of cardiac homeostasis, triggering heart dysfunction. Although the role of some histone methyltransferases in establishing the transcriptional program of postnatal cardiomyocytes during heart development has been shown, the function of this class of epigenetic enzymes is largely unexplored in the adult heart. In this study, we investigated the role of G9a/Ehmt2, a histone methyltransferase that defines a repressive epigenetic signature, in defining the transcriptional program for cardiomyocyte homeostasis and cardiac hypertrophy. METHODS: We investigated the function of G9a in normal and stressed cardiomyocytes with the use of a conditional, cardiacspecific G9a knockout mouse, a specific G9a inhibitor, and highthroughput approaches for the study of the epigenome (chromatin immunoprecipitation sequencing) and transcriptome (RNA sequencing); traditional methods were used to assess cardiac function and cardiovascular disease. RESULTS: We found that G9a is required for cardiomyocyte homeostasis in the adult heart by mediating the repression of key genes regulating cardiomyocyte function via dimethylation of H3 lysine 9 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, and MEF2C-dependent gene expression by forming a complex with this transcription factor. The G9a-MEF2C complex was found to be required also for the maintenance of heterochromatin needed for the silencing of developmental genes in the adult heart. Moreover, G9a promoted cardiac hypertrophy by repressing antihypertrophic genes. CONCLUSIONS: Taken together, our findings demonstrate that G9a orchestrates critical epigenetic changes in cardiomyocytes in physiological and pathological conditions, thereby providing novel therapeutic avenues for cardiac pathologies associated with dysregulation of these mechanisms.

AB - BACKGROUND: Correct gene expression programming of the cardiomyocyte underlies the normal functioning of the heart. Alterations to this can lead to the loss of cardiac homeostasis, triggering heart dysfunction. Although the role of some histone methyltransferases in establishing the transcriptional program of postnatal cardiomyocytes during heart development has been shown, the function of this class of epigenetic enzymes is largely unexplored in the adult heart. In this study, we investigated the role of G9a/Ehmt2, a histone methyltransferase that defines a repressive epigenetic signature, in defining the transcriptional program for cardiomyocyte homeostasis and cardiac hypertrophy. METHODS: We investigated the function of G9a in normal and stressed cardiomyocytes with the use of a conditional, cardiacspecific G9a knockout mouse, a specific G9a inhibitor, and highthroughput approaches for the study of the epigenome (chromatin immunoprecipitation sequencing) and transcriptome (RNA sequencing); traditional methods were used to assess cardiac function and cardiovascular disease. RESULTS: We found that G9a is required for cardiomyocyte homeostasis in the adult heart by mediating the repression of key genes regulating cardiomyocyte function via dimethylation of H3 lysine 9 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, and MEF2C-dependent gene expression by forming a complex with this transcription factor. The G9a-MEF2C complex was found to be required also for the maintenance of heterochromatin needed for the silencing of developmental genes in the adult heart. Moreover, G9a promoted cardiac hypertrophy by repressing antihypertrophic genes. CONCLUSIONS: Taken together, our findings demonstrate that G9a orchestrates critical epigenetic changes in cardiomyocytes in physiological and pathological conditions, thereby providing novel therapeutic avenues for cardiac pathologies associated with dysregulation of these mechanisms.

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KW - Hypertrophy

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