Epigenetics in Cardiac Hypertrophy and Heart Failure

Abstract

Heart failure (HF) is a complex syndrome affecting millions of people around the world. Over the past decade, the therapeutic potential of targeting epigenetic regulators in HF has been discussed extensively. Recent advances in next-generation sequencing techniques have contributed substantial progress in our understanding of the role of DNA methylation, post-translational modifications of histones, adenosine triphosphate (ATP)-dependent chromatin conformation and remodeling, and non-coding RNAs in HF pathophysiology. In this review, we summarize epigenomic studies on human and animal models in HF.

Keywords: BET, bromodomain; EZH2, Enhancer of zeste homolog 2; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; HF, heart failure; HMT, histone methyltransferase; PRC2, polycomb repressor complex 2; PTMs, post-translational modifications; TAD, topologically associating domains; TMAO, trimethylamine N-oxide; cardiac hypertrophy; epigenetics; heart failure; lnc-RNAs, long ncRNAs.

Graphical abstract

Figure 1

The Epigenetic Mechanisms in Heart Failure Epigenetic regulations include DNA methylation, PTMs of histones, ATP-dependent chromatin conformation and remodeling, and non-coding RNA-mediated regulation. DNA methylated CpG-enriched region at the promoter region of genes is often associated with gene silencing, whereas methylated CpG found in the gene body is usually related to gene activation. Histone modifications associated with gene expression normally occur on histone 3. The histone writers (HAT and HMT) and erasers (HDAC and HMT) are responsible for PTMs of histone. The active histone mark, H3K27ac and repressive marks, H3K9me2 and H3k27me3, and promoter mark, H3K4me3, are shown. LncRNA can work with epigenetic regulators to effect activation or repression on chromosome remodeling and accessibility as well as the mRNA stability. In the non-failing heart, normal adult cardiac genes, adult isoform MYH6, express normally in cardiomyocyte. The cardiac hypertrophy genes, such as NPPA and CTGF, are not expressed or are at a basal level in non-failing hearts. The DNA around the promoter region of the hypertrophic-related gene loci is hypermethylated, and the chromatin state is inactive by marking H3K27me3 and/or H3K9me2. The PRC2/EZH2 and G9a-EZH2-MEF2C complexes involved in histone methylation in normal hearts are shown. It was shown that lncRNA, Mhrt, plays a critical role in maintaining MYH6 expression in the adult heart by preventing BRG1 binding to the promoter region of MYH6. However, in failing hearts, in addition to normal cardiac gene expression, the hearts return to the fetal gene program and express the fetal isoform of myosin heavy chain, MYH7. This is likely due to the re-activation of BRG1 during heart failure. The potential mechanisms are shown. Two cardiac transcription factors, GATA4, MEF2C, and CBP/p300 (HAT), and JMJD (HMT) are involved in cardiac hypertrophy and heart failure. Two examples of the actions of lncRNAs, CHRT and Chaer, involved in cardiac hypertrophy and heart failure are presented. (Please see text for details.) ATP = adenosine triphosphate; CpG = cytosine-phosphate-guanine ; HAT = histone acetyltransferase; HDAC = histone deacetylase; HMT = histone methyltransferase; mRNA = messenger RNA; MYH6 = myosin heavy chain; MYH7 = myosin heavy chain beta; PTM = post-translational modifications.

Central Illustration

The Epigenetic Mechanisms in Heart Failure