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. The word “epigenetics” is composed of a Greek prefix, “epi,” meaning “upon,” “on,” or “around” and the word “genetics.” Therefore, epigenetics can be defined as the mechanism that affects heritable changes in gene expression and function without alternating the sequence of the genome. It plays fundamental roles in regulating the architecture of chromatins and gene expression at various molecular levels for maintaining cell identity and controlling cell differentiation, which are critically important for normal development and diseases. Changes of the epigenome are hallmarks of various cancers and several potentially molecules have been identified as potential new drug therapies. The study of epigenetics in cardiovascular diseases is a relatively new field. Heart failure (HF), being the leading cause of death worldwide, occurs when the myocardium has long been recognized to undergo structural and functional remodeling. Such processes may be the cause and/or consequence of various genomic and transcriptional reprogramming of the cardiomyocytes and other nearby cells. Hence, better understanding of how epigenetic regulations are involved in HF may open a new perspective for translational research into new diagnostic tools as well as novel strategies in drug design and discovery. Epigenetic regulation can be classified at 4 different molecular levels: 1) DNA methylation, 2) post-translational modifications of histones, 3) adenoisine triphosphate (ATP)-dependent chromatin conformation and remodeling, and 4) non-coding RNAs.

ATP-Dependent Chromatin Conformation, Remodeling, and HF

The mammalian chromatin architecture and organization are highly regulated. The dynamic modification of the epigenome, including post-translational modification on histone tails and DNA methylation, causes chromatin remodeling and re-organization. This is an important process for controlling cell-fate determination, differentiation, and organ development. The chromatin regulators, such as histone modifiers, co-factors, and transcriptional regulators, can recruit or be recruited by other chromatin regulators and transcription factors to regulate gene expression. By recruiting all necessary regulators, the distal cis-acting elements, such as enhancers, can form chromatin loops to interact with the proximal promoter regions of genes, and thus initiate and enhance the transcriptional activity of genes with the basal transcriptional complex. chromosome conformation capture technique approach, Hi-C, to create the 3D map of the chromosome interaction for induced pluripotent stem cell-derived cardiomyocytes, Montefiori et al. recently linked the known cardiovascular disease–associated single nucleotide polymorphism to the target genes. The authors identified that the majority of non-coding regions could influence genes that are far away from them and some regions may modulate the gene expression for more than 2 genes. These findings are consistent with the notions that the long distance enhancers interact with the promoter to establish a long-range control of gene expression, and it is important to consider this aspect when interpreting functional targets of disease loci.

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