Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo

Ralf Gilsbach,Pedro Schneider,Lutz Hein,Martin Schwaderer,Markus Krane,Sebastian Preissl,Sonia Mulero-Navarro,David Kranzhöfer,Rolf Backofen,Bruce D Gelb,Harald Lahm,Adam R Jacobs,Dieter Weichenhan,Thomas G Nührenberg,Björn A Grüning,Christian Braun,Martina Dreßen,Torsten Doenst

doi:10.1038/s41467-017-02762-z

Abstract

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping of the epigenome of these terminally differentiated cells during fetal development, postnatal maturation, and in disease remains unknown. Here, we investigate the dynamics of the cardiac myocyte epigenome during development and in chronic heart failure. We find that prenatal development and postnatal maturation are characterized by a cooperation of active CpG methylation and histone marks at cis-regulatory and genic regions to shape the cardiac myocyte transcriptome. In contrast, pathological gene expression in terminal heart failure is accompanied by changes in active histone marks without major alterations in CpG methylation and repressive chromatin marks. Notably, cis-regulatory regions in cardiac myocytes are significantly enriched for cardiovascular disease-associated variants. This study uncovers distinct layers of epigenetic regulation not only during prenatal development and postnatal maturation but also in diseased human cardiac myocytes.

Highlights

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered
The detailed epigenetic processes involved in maturation from fetal to adult cardiac myocytes (CMs) and in cardiac disease leading to terminal heart failure have not been fully uncovered, yet
We find that during normal lifespan of CMs gene regulation is mainly orchestrated by dynamic mCpG and canonical histone marks at distal regulatory and genic regions

Summary

Introduction

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. The general principles of cardiac development have been studied in great detail on a morphological and molecular basis These studies have identified key signaling events and transcription factor networks that are involved in the specification and differentiation of cardiac myocytes (CMs)[1,2,3,4,5,6]. Purification of CM nuclei by fluorescence-assisted sorting has led to the identification of cell-type-specific mCpG and histone modification signatures in CMs during mouse heart development and maturation[11] Based on this method[13,14], we used a nuclear staining strategy to isolate CM nuclei from intact prenatal and postnatal human heart tissue and subjected these nuclei to comprehensive analysis of the epigenome during prenatal development, postnatal maturation, and in heart failure. Linking this functional annotation with known genetic polymorphisms revealed the presence of cardiovascular diseaseassociated polymorphisms in active CM enhancers

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Results

Conclusion