Epigenetics in dilated cardiomyopathy

Abstract

Purpose of review: Characterized by enlarged ventricle and loss of systolic function, dilated cardiomyopathy (DCM) has the highest morbidity among all the cardiomyopathies. Although it is well established that DCM is typically caused by mutations in a large number of genes, there is an emerging appreciation for the contribution of epigenetic alteration in the development of DCM.

Recent findings: We present some of the recent progress in the field of epigenetics in DCM by focusing on the four major epigenetic modifications, that is, DNA methylation, histone modification, chromatin remodeling as well as the noncoding RNAs. The major players involved in these DCM-related epigenetic reprogramming will be highlighted. Finally, the diagnostic and the therapeutic implications for DCM based on new knowledge of epigenetic regulation will also be discussed.

Summary: As a rapidly expanding field, epigenetic studies in DCM have the promise to yield both novel mechanistic insights as well as potential new avenues for more effective treatment of the disease.

FIGURE 1

DNA methylation and demethylation pathways. (a) DNA methyltransferases (DNMTS) catalyzes the transfer of a methyl group to the cytosine forming the 5-methylcytosine (5mC), which is the DNA methylation process. The demethylation of methylated DNA can be catalyzed by different mechanisms. The amine group of 5mC can be deaminated by AID/APOBEC, converting 5mC into thymine (T). Also the methyl group of 5mC can be modified by the addition of a hydroxyl group mediated by Tet enzymes to generate 5-hydroxymethyl-cytosine (5hmC). Then 5hmC can be chemically modified at two sites: the amine group and the hydroxymethyl group. AID/APOBEC can deaminate 5hmC to produce 5-hydroxymethyl-uracil (5hmU). And TET can further oxidize 5hmC to form 5-formyl-cytosine (5fC) and then 5-carboxy-cytosine (5caC). Eventually, Thymine, 5hmU, 5fC, and 5caCF are recognized and cleaved off to replace with a naked cytosine through the base excision repair pathway by TDG and/or SMUG1. (b) Functional impact of DNA methylation on gene expression. Hypermethylation in the CpG islands of promoters and intergenic regions tend to repress transcription activities. Hyper-DNA methylation in the gene bodies is correlated with a higher level of transcription in dividing cells, but not associated in slow growing or nondividing cells.

FIGURE 2

Epigenetics in dilated cardiomyopathy. (a) DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs are the main key epigenetic regulatory processes and players, (b) Specific pathogenic processes of DCM implicated by epigenetic regulation, including metabolism dysfunction, cardiomyocyte apoptosis, sarcomere disorganization, and contractile dysfunction. (c) These converging features contribute to phenotype of DCM. (Depiction in panels a and b partially derived from online materials from Smart Service Medical Art under Creative Commons https://creativecommons.org/licenses/by/3.0/) Links to the figures - https://smart.servier.com/smart_image/dna-14/; https://smart.servier.com/smart_image/chromosome-9/; https://smart.servier.com/smart_image/mitochondria-7/; https://smart.servier.com/smart_image/cardiomyocyte-9/; https://smart.servier.com/smart_image/muscle-9/ https://smart.servier.com/smart_image/cellules-coeur/.