Translational Perspective on Epigenetics in Cardiovascular Disease

Abstract

A plethora of environmental and behavioral factors interact, resulting in changes in gene expression and providing a basis for the development and progression of cardiovascular diseases. Heterogeneity in gene expression responses among cells and individuals involves epigenetic mechanisms. Advancing technology allowing genome-scale interrogation of epigenetic marks provides a rapidly expanding view of the complexity and diversity of the epigenome. In this review, the authors discuss the expanding landscape of epigenetic modifications and highlight their importance for future understanding of disease. The epigenome provides a mechanistic link between environmental exposures and gene expression profiles ultimately leading to disease. The authors discuss the current evidence for transgenerational epigenetic inheritance and summarize the data linking epigenetics to cardiovascular disease. Furthermore, the potential targets provided by the epigenome for the development of future diagnostics, preventive strategies, and therapy for cardiovascular disease are reviewed. Finally, the authors provide some suggestions for future directions.

Keywords: EWAS; HAT; HDAC; RNA; histones; methylation.

Figure 1. Epigenetic Modifications and Their Location

Epigenetics is the collective name for the genetic effects resulting in gene expression but do not involve variation in the DNA sequence itself. These include the chemical modifications to DNA itself (DNA methylation), the histones (around which DNA is wound) or non-coding RNA. Eight histone unit form chromatin, around which 146 bp of DNA is wound to form the nucleosome. (A) The histone tails can have multiple marks. (B) Histone-modifying enzymes. (C) DNA methylation occurs predominantly at the CpG islands. (Middle lower box) Epigenetic marks are important determinant of the differentiation and cell fate during development. (Lower right corner) (A) Certain modifications can increase accessibility to DNA. (B) Histone complexes can have modifications at multiple positions on the tail, jointly making up the histone code. (C) Histone-remodeling complex slide histones in directions, making the DNA accessible or not.

Figure 2. Noncoding RNA

(A) Schematic overview of the transcriptome and the classification of RNA as coding or noncoding, with the different species of noncoding RNA. (B) Different mechanisms of action of noncoding RNAs in epigenetic regulation. circRNA = circular RNA; lncRNA = long noncoding RNA; Me = methyl; miRNA = microRNA; ORF = open reading frame; piRNA = Piwi-interacting RNA; rasiRNA = repeat-associated small interfering RNA; RISC = RNA-induced silencing complex; RNA pol = RNA polymerase; scaRNA = small Cajal body-specific RNA; siRNA = small interfering RNA; snoRNA = small nucleolar RNA; snRNA = small nuclear RNA; tiRNA = transcription initiation RNA;

Central Illustration. Potential Therapeutic Epigenetic Targets in Cardiovascular Disease

Examples of targeting epigenetic mechanisms in CVD. Possible targets include modifying DNA methylation, changing the acetylation or deacytylation of histones, and miRNA or lncRNA modificiations. DNMT = DNA methyltransferase; HAT = histone acetyltransferase; HDAC = histone deacetylase; lncRNA = long noncoding RNA; miRNA = microRNA.