Roberto Papait1, Simone Serio2, Christina Pagiatakis2, Francesca Rusconi2, Pierluigi Carullo2, Marta Mazzola2, Nicolò Salvarani2, Michele Miragoli2, Gianluigi Condorelli1. 1. From Department of Cardiovascular Medicine, Humanitas Research Hospital, Rozzano, Milan, Italy (R.P., S.S., C.P., F.R., P.C., N.S., M. Miragoli, G.C.); Genetic and Biomedical Research Institute, National Research Council of Italy, Rozzano, Milan, Italy (R.P., F.R., P.C., N.S., G.C.); Humanitas University, Rozzano, Milan, Italy (M. Mazzola, G.C.); School of Medicine, University of Verona, Italy (M. Mazzola); and Department of Medicine and Surgery, University of Parma, Italy (M. Miragoli). roberto.papait@humanitasresearch.it gianluigi.condorelli@hunimed.eu. 2. From Department of Cardiovascular Medicine, Humanitas Research Hospital, Rozzano, Milan, Italy (R.P., S.S., C.P., F.R., P.C., N.S., M. Miragoli, G.C.); Genetic and Biomedical Research Institute, National Research Council of Italy, Rozzano, Milan, Italy (R.P., F.R., P.C., N.S., G.C.); Humanitas University, Rozzano, Milan, Italy (M. Mazzola, G.C.); School of Medicine, University of Verona, Italy (M. Mazzola); and Department of Medicine and Surgery, University of Parma, Italy (M. Miragoli).
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, cardiac-specific G9a knockout mouse, a specific G9a inhibitor, and high-throughput 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.
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, cardiac-specific G9a knockout mouse, a specific G9a inhibitor, and high-throughput 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.
Authors: Amelia Weber Hall; Mark Chaffin; Carolina Roselli; Honghuang Lin; Steven A Lubitz; Valerio Bianchi; Geert Geeven; Kenneth Bedi; Kenneth B Margulies; Wouter de Laat; Nathan R Tucker; Patrick T Ellinor Journal: Circ Genom Precis Med Date: 2020-11-06
Authors: Ralf Gilsbach; Martin Schwaderer; Sebastian Preissl; Björn A Grüning; David Kranzhöfer; Pedro Schneider; Thomas G Nührenberg; Sonia Mulero-Navarro; Dieter Weichenhan; Christian Braun; Martina Dreßen; Adam R Jacobs; Harald Lahm; Torsten Doenst; Rolf Backofen; Markus Krane; Bruce D Gelb; Lutz Hein Journal: Nat Commun Date: 2018-01-26 Impact factor: 14.919