Abstract
Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterised by the excessive deposition of extracellular matrix proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Although a considerable amount of research has focused on the mechanisms underlying disease pathogenesis, current therapeutic options do not directly target the pro-fibrotic process. As a result, there is a clear unmet clinical need to develop new agents. Novel findings implicate a role for epigenetic modifications contributing to the progression of fibrosis by alteration of gene expression profiles.This review will focus on DNA methylation; its association with fibroblast differentiation and activation and the consequent buildup of fibrotic scar tissue. The potential use of therapies that modulate this epigenetic pathway for the treatment of fibrosis in several organ systems is also discussed.
Highlights
Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue
This work suggests a positive relationship between MeCP2 expression and the development of fibrosis, but the authors of this study focus on pro-fibrotic alpha smooth muscle actin (αSMA) expression
The authors in this paper link reduced MeCP2 with reduced fibrosis due to profibrotic gene silencing. Whilst both studies support a pro-fibrotic function for MeCP2, these data suggest an alternate mechanism to the work carried out by Tao et al who associate reduced MeCP2 with reduced methylation, transcriptional activation of antifibrotic Ras GTPase activating-like protein 1 (RASAL1)/peroxisome proliferator-activated receptor gamma (PPARλ). These findings suggest that the effects of transcriptional repression by MeCP2 may be gene-/species-dependent or that perhaps complete knockout of MeCP2 has knock-on effects on other associated pathways which may contribute to the effects on αSMA expression
Summary
Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue. Several murine models of cardiac disease support a pathogenic role for DNA methylation in myocardial fibrosis and highlight beneficial effects upon therapeutic intervention with inhibitors of this epigenetic process.
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