The Histone Methyl-transferase G9a Defines the Epigenetic Landscape Underlying of the Homeostasis of Heart and the Cardiac Hypertrophy

Cardiac hypertrophy is an initially adaptive response of the myocardium to increased work overload that can progress to heart failure (HF)1. At the molecular level, it is associated with a specific gene expression program2. The role of histone methylation in regulating this program is poorly understood. Our group has shown that an epigenetic signature defined by methylation and acetylation of histone H3 regulates the gene expression changes accompanying cardiac hypertrophy3. However, the molecular pathways that define this signature are not elucidated yet. To try to answer this question, we will investigate the function of G9a - a histone methyl-transferase able to mono- and di-methylate histone H3 at Lys9, and to a lesser extent at Lys27- in cardiac hypertrophy and cardiomyocyte homeostasis. Here, we show that the histone methyltransferase G9a/Ehmt2 has a key role in maintaining cardiomyocyte homeostasis, repressing key genes of heart function through the dimethylation of lysine 9 of histone H3 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2. We also found that G9a represses the transcriptional activity of MEF2C on genes encoding contractility and calcium signalling proteins, and that the G9a–MEF2C complex is required for the maintenance of heterochromatin regions responsible for the silencing of key genes of heart developmental. Moreover, G9a is up-regulated in initial stages of cardiac hypertrophy and it promotes cardiac hypertrophy by repressing anti-hypertrophic genes. These findings support a dual role for G9a in the heart: in the normal heart, G9a acts in an anti-hypertrophic manner, whereas in the stressed heart it promotes cardiac hypertrophy4.