Epigenetic mechanisms in heart failure pathogenesis.

A lthough neurohormonal antagonist and device therapies have improved outcomes in patients with systolic heart failure (HF), residual morbidity and mortality remain high. Novel HF therapeutic approaches thus remain an unmet clinical need of pressing urgency. Such approaches depend, in turn, on keener understanding of the molecular pathways underlying HF pathogenesis. Although a number of novel myocardial signaling effectors have been implicated as drivers of HF pathogenesis, 1,3 translating these findings into human therapies has remained extremely challenging. Gene expression profiling studies in animal HF models 4 and in human failing hearts 5 consistently demonstrate aberrant gene control in HF. The term epigenetics—a fusion of epigenesis and genetics—was coined ≥50 years ago to describe the process of cell fate commitment during development. 6 Today, the epigenome denotes the totality of sequence-independent processes that modulate cell-state–specific gene expression (eg, post-translational histone or DNA modifications and noncoding RNA/protein complex interactions with chromatin). 7–10 The epigenome may differ between cell types, drive local formation of higher order chroma-tin structures, modulate transcription factor (TF) access to DNA, and preserve memory of past transcriptional activities. 10 This review focuses on the chromatin-specific epigenetic regulatory mechanisms that may inform novel therapeutic targets in HF. We specifically highlight examples of chroma-tin remodeling, biochemical modifications to histones, and integrated features of chromatin-dependent signal transduc-tion that are pertinent to cardiac biology. Other epigenetic pathways in HF, including miRNAs, have been extensively reviewed elsewhere. Eukaryotic cell identity or more broadly, cellular state, is largely governed by precise spatiotemporal coordination of gene expression. 9 Pathological transformation from a normal to a diseased cardiomyocyte (eg, hypertrophied and hypocon-tractile) represents a cell state transition driven by defined transcriptional events. Dynamic interplay among accessible DNA sequences, chromatin-binding TFs, and associated DNA/RNA-binding proteins alter local chromatin structure to orchestrate gene expression programs. To provide a necessary framework for this review, we first briefly summarize some fundamental features of eukaryotic gene regulation 9,13 Chromatin In the nucleus of every cell, >1 m of linear DNA is densely com-pacted into chromatin, 14 a dynamic macromolecular complex of DNA, RNA, and diverse proteins (Figure 1). The fundamental primary unit of chromatin is the nucleosome core particle, composed of ≈147 bp of double-stranded DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4. 15 The histones within nucleosomes can be dynamically modified and exchanged …