Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

Abstract

Cardiac fibrosis is a common pathophysiologic process associated with numerous cardiovascular diseases, resulting in cardiac dysfunction. Cardiac fibroblasts (CFs) play an important role in the production of the extracellular matrix and are the essential cell type in a quiescent state in a healthy heart. In response to diverse pathologic stress and environmental stress, resident CFs convert to activated fibroblasts, referred to as myofibroblasts, which produce more extracellular matrix, contributing to cardiac fibrosis. Although multiple molecular mechanisms are implicated in CFs activation and cardiac fibrosis, there is increasing evidence that epigenetic regulation plays a key role in this process. Epigenetics is a rapidly growing field in biology, and provides a modulated link between pathological stimuli and gene expression profiles, ultimately leading to corresponding pathological changes. Epigenetic modifications are mainly composed of three main categories: DNA methylation, histone modifications, and non-coding RNAs. This review focuses on recent advances regarding epigenetic regulation in cardiac fibrosis and highlights the effects of epigenetic modifications on CFs activation. Finally, we provide some perspectives and prospects for the study of epigenetic modifications and cardiac fibrosis.

Keywords: epigenetics; fibroblasts; fibrosis; heart.

Figure 1

Cardiac fibroblasts activation and cardiac fibrosis. Activation of CFs into myofibroblasts is the cellular biological basis of cardiac fibrosis. Resident fibroblasts contribute to the maintenance of cardiac structure and homeostasis in a healthy heart. Under diverse pathologic stress and environmental stress, resident CFs in the injured heart are activated as myofibroblasts, infiltrate and proliferate in the injured area, synthesize and deposit excessive ECM, and eventually lead to the occurrence of cardiac fibrosis.

Figure 2

DNA methylation modifications regulate fibrosis-related genes involved in CFs activation and cardiac fibrosis. DNMTs and TETs cooperate to regulate DNA methylation levels, which determines the transcriptional activity of fibrotic genes as well as induces cardiac fibrosis. DNMTs as writers drive DNA methylation, repress transcription, and silence anti-fibrotic genes. Conversely, erasers’ TETs-mediated DNA demethylation activate transcription and involve in the activation of pro-fibrotic genes. As shown in the figure, different colors suggest that different genes and epigenetic-modifying enzymes play different roles in cardiac fibrosis. The application of DNMTi can target to alleviate DNA methylation-regulated cardiac fibrosis.

Figure 3

Histone acetylation modifications regulate fibrosis-related genes involved in CFs activation and cardiac fibrosis. The processes of histone acetylation and deacetylation are dynamically reversible, and histone acetylation modification states determine the chromatin accessibility as well as further transcriptional activity of fibrotic genes. HATs as writers and BRD4 as readers enhance chromatin accessibility and activate transcription, promoting pro-fibrotic gene expression. Conversely, HDACs mediate deacetylation as erasers, which reduce chromatin accessibility, repress transcription and participate in the epigenetic silencing of anti-fibrotic genes. As shown in the figure, different colors suggest different genes, and epigenetic-modifying enzymes play different roles in cardiac fibrosis. The application of p300i, BETi, and HDACi can target to alleviate histone acetylation-regulated cardiac fibrosis.

Figure 4

Histone methylation modifications regulate fibrosis-related genes involved in CFs activation and cardiac fibrosis. Histone methylation and demethylation are dynamic and reversible, and histone methylation modification sites and status determine chromosome accessibility and further transcriptional activity of fibrotic genes. Not only do writers KMTs drive H3K9me2, reducing chromatin accessibility and repressing transcription to silence anti-fibrotic genes, but they also drive H3K79me2, increasing chromatin accessibility, activating transcription, and promoting pro-fibrotic gene expression. Conversely, KDMs remove methyl from H3K9me2/3, which increases chromatin accessibility, promotes transcription, and is involved in the activation of pro-fibrotic genes. As shown in the figure, different colors suggest different genes, and epigenetic-modifying enzymes play different roles in cardiac fibrosis. The application of EZH2i can target the alleviation of histone methylation-regulated cardiac fibrosis.

Figure 5

RNA regulates transcriptional and translational processes through multi-level ncRNA and RNA modifications involved in CFs activation and cardiac fibrosis. Multi-level of ncRNAs (e.g., miRNAs and lncRNAs) play cardiac pro-fibrotic and anti-fibrotic roles. In addition, m⁶A affects the expression of fiber-associated proteins by regulating the level of mRNA methylation. m⁶A modification process is dynamically reversible and co-regulated by METTL3 and FTO in CFs. As shown in the figure, different colors suggest that different ncRNA and epigenetic-modifying enzymes play different roles in cardiac fibrosis.