Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

Abstract

Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, considerable efforts have been made to understand the molecular mechanisms underlying fibrotic evolution and to identify possible therapeutic strategies. Great interest has been aroused by the discovery of a molecular association between epithelial to mesenchymal plasticity (EMP), in particular epithelial to mesenchymal transition (EMT), and fibrogenesis, which has led to the identification of complex molecular mechanisms closely interconnected with each other, which could explain EMT-dependent fibrosis. However, the result remains unsatisfactory from a therapeutic point of view. In recent years, advances in epigenetics, based on chromatin remodeling through various histone modifications or through the intervention of non-coding RNAs (ncRNAs), have provided more information on the fibrotic process, and this could represent a promising path forward for the identification of innovative therapeutic strategies for organ fibrosis. In this review, we summarize current research on epigenetic mechanisms involved in organ fibrosis, with a focus on epigenetic regulation of EMP/EMT-dependent fibrosis.

Keywords: DNA methylation; epigenetic; fibrosis; histone modification; inflammation; ncRNA.

Figure 1

Schematic representation of epithelial to mesenchymal plasticity (EMP). EMP, in response to epithelial injury, allows cells to convert between multiple states across the epithelial to mesenchymal transformation, acquiring hybrid epithelial/mesenchymal phenotypic features.

Figure 2

A schematic overview of epigenetic modifications. Epigenetic regulation involves DNA methylation, histone modification, and non-coding RNAs. DNMT family members mediate DNA methylation, which suppresses gene transcription by adding a methyl group to the cytosine position. Histone methylation is catalyzed by HMTs and HDMTs, and histone acetylation is regulated by HATs and HDACs. Non-coding RNAs include miRNAs, circRNAs, and lncRNAs. BET (Bromodomain and extraterminal); BRMDs (bromodomains); DNMT (DNA methyltransferase); HATs (Histone acetylases); HDACs (Histone deacetylases); HDMTs (Histone demethylases); HMTs (Histone methyltransferases); lncRNA (long non-coding RNA); TET (Ten-eleven translocation).

Figure 3

Scheme of the epigenetic modifications in EMP/EMT-dependent fibrotic diseases. DNMT (DNA methyltransferase); HAT (Histone acetylase); HDAC (Histone deacetylase); EndMT (Endothelial–mesenchymal transition); EMT (Epithelial–mesenchymal transition); SOCS3 (cytokine signaling 3); VAP (Valproic acid).