Epigenetics as a versatile regulator of fibrosis

Abstract

Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications. Graphical Abstract

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…The transcriptional regulation driven by the DNA methylation pattern plays a pivotal role in liver fibrosis [ 10 ]. In particular, DNA methylation is involved in the differentiation of HSC during hepatic diseases characterized by a severe and progressive fibrotic process.…”

“…In particular, HATs regulate gene silencing or transcription through the modulation of the acetylation of histones, thus orchestrating gene expression to induce liver fibrosis [ 110 , 111 ]. Additionally, histone acetylation has been implied in pulmonary and cardiac fibrosis [ 10 ], performed through the activity of p300 HAT [ 112 , 113 ]. An interesting discovery enriched the molecular scenario by demonstrating that p300 HAT induces the fibrotic process in IPF and cardiac fibrosis via EMT and EndMT, respectively [ 114 ].…”

“…Supporting the role of histone acetylation in EMT-dependent fibrotic diseases, HDAC7 has also been demonstrated to regulate collagen deposition and other ECM protein accumulation in fibroblasts derived from patients affected by systemic sclerosis, and indeed, siRNA-mediated depletion of HDAC7 reduced ECM production in these cells, resulting in an evident decrease in fibrogenesis [ 10 ]. However, the mechanism of action of class IIb HDACs in the fibrotic process will certainly require further investigation.…”

“…Despite the fact that fibrosis appears to be a partly reversible process in various clinical studies [ 9 ], unfortunately, therapeutic options are still very limited. In recent years, very innovative studies have demonstrated how epigenetic modifications, by triggering or inhibiting gene transcription depending on the circumstances, can reprogram gene expression by adapting it to exposure to various risk factors [ 10 ]. This has been demonstrated, for example, in idiopathic pulmonary fibrosis (IPF) or in patients with non-alcoholic fatty liver disease, in which biopsy samples show higher expression of DNA methyltransferase, suggesting that DNA methylation could represent a predisposing factor for the onset of these pathologies [ 11 ].…”

“…Some authors have described in detail the mechanisms through which the main epigenetic modifications would act, inducing a regulation of the fibrotic evolution of the inflammatory processes and determining the transcription of pro-fibrotic genes [ 12 ]. In addition, epigenetics could explain the reversibility of the fibrosis [ 10 ]. However, although recent discoveries tend toward the involvement of epigenetic modifications in EMP/EMT-dependent fibrosis, the elucidation of the mechanisms involved still seems far from clear.…”