The role of H3K9 methylation by Euchromatic Histone Methyl Transferases (EHMT1/2) in controlling cardiac myocyte growth and proliferative responses during health and disease.

Heart disease is a leading cause of mortality and morbidity in the western world. Owing to the post-mitotic, terminally differentiated nature of its constituent myocytes (CMs) and thus ita poor regenerative capacity, transplant is the only therapy available for the failing heart. We have identified a novel ‘epigenetic’ mechanism by which the expression of genes associated with fetal stages and those involved in cell proliferation is repressed in the adult heart but reactivated during pathology, contributing to associated decline in cardiac function. Intriguingly, this epigenetic mechanism involving histone methylation also contributes to repressing the expression of cell cycle genes underlying the transition of the CM from a mitotic neonate to the post-mitotic adult state. As for the fetal gene programme, these genes are also re-activated in disease. Together, our data provide a mechanism by which adult cardiac myocytes are locked in their post-mitotic state throughout their lifetime. Here we test the hypothesis that manipulation of the epigenetic processes identified (epigenetic rejuvenation) provides a strategy to enhance CM proliferation and thus the repair capacity of the heart and to reverse deleterious hypertrophy of the existing myocytes in the heart.

Keywords:Cardiac Diseases, Cardiac Regeneration, Epigenetics, Next Generation Sequencing, Histone Methylation, Transcriptional Regulation, Bioinformatics

Disciplines:Other biological sciences, Scientific computing, Bioinformatics and computational biology, Public health care, Public health services, Cardiac and vascular medicine, Biochemistry and metabolism, Medical biochemistry and metabolism