Chromatin remodelling and epigenetic state regulation by non-coding RNAs in the diseased heart

Abstract

Epigenetics refers to all the changes in phenotype and gene expression which are not due to alterations in the DNA sequence. These mechanisms have a pivotal role not only in the development but also in the maintenance during adulthood of a physiological phenotype of the heart. Because of the crucial role of epigenetic modifications, their alteration can lead to the arise of pathological conditions. Heart failure affects an estimated 23 million people worldwide and leads to substantial numbers of hospitalizations and health care costs: ischemic heart disease, hypertension, rheumatic fever and other valve diseases, cardiomyopathy, cardiopulmonary disease, congenital heart disease and other factors may all lead to heart failure, either alone or in concert with other risk factors. Epigenetic alterations have recently been included among these risk factors as they can affect gene expression in response to external stimuli. In this review, we provide an overview of all the major classes of chromatin remodellers, providing examples of how their disregulation in the adult heart alters specific gene programs with subsequent development of major cardiomyopathies. Understanding the functional significance of the different epigenetic marks as points of genetic control may be useful for developing promising future therapeutic tools.

Fig. 1

Epigenetic regulation results in gene expression without involving variations in the DNA sequence itself; epigenetic mechanisms include chemical modifications of the DNA (DNA methylation) and of the histones and non-coding RNAs. (A) DNA methylation occurs predominantly at the CpG islands. (B) Histone complexes can be modified, such as by the addition of methyl- and acetyl-groups, by ubiquitination or SUMOylation, at multiple positions on the tail. The major modification positions are reported: red-methylation, dark blue-phosphorylation, green-acetylation, blue-ubiquitination. (C) Histone-remodelling complexes slide or displace histones, modifying DNA accessibility.

Fig. 2

Scheme representing the principal epigenetic regulations in heart failure development.

Fig. 3

miRNAs biogenesis and function.