DNA methylation regulated gene expression in organ fibrosis

Abstract

DNA methylation is a major epigenetic mechanism to regulate gene expression. Epigenetic regulation, including DNA methylation, histone modifications and RNA interference, results in heritable changes in gene expression independent of alterations in DNA sequence. Epigenetic regulation often occurs in response to aging and environment stimuli, including exposures and diet. Studies have shown that DNA methylation is critical in the pathogenesis of fibrosis involving multiple organs sytems, contributing to significant morbidity and mortality. Aberrant DNA methylation can silence or activate gene expression patterns that drive the fibrosis process. Fibrosis is a pathological wound healing process in response to chronic injury. It is characterized by excessive extracellular matrix production and accumulation, which eventually affects organ architecture and results in organ failure. Fibrosis can affect a wide range of organs, including the heart and lungs, and have limited therapeutic options. DNA methylation, like other epigenetic process, is reversible, therefore regarded as attractive therapeutic interventions. Although epigenetic mechanisms are highly interactive and often reinforcing, this review discusses DNA methylation-dependent mechanisms in the pathogenesis of organ fibrosis, with focus on cardiac and pulmonary fibrosis. We discuss specific pro- and anti-fibrotic genes and pathways regulated by DNA methylation in organ fibrosis; we further highlight the potential benefits and side-effects of epigenetic therapies in fibrotic disorders.

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

“…Epigenetic mechanisms may govern the accumulation of collagen by reducing promoter methylation and increasing expression of collagen genes (34,35). Disruption of this epigenetic!collagen axis is considered as the main cause of the deregulation of collagen deposition during aging and in pathological conditions, including tumorigenesis (36).…”

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

“…Epigenetic changes after stress insult could theoretically be a direct consequence of responses involving changes to cell development or cell composition. For example, tissue fibrotisation resulting from a given stress could potentially shift bulk methylation to a more fibroblast‐like state (Maierhofer et al ., ; Zhang et al ., ; Negreros et al ., ) and thus represent an indirect marker of exposure. Future studies should aim to clarify how epigenetic responses occurring at different development stages influence organismal sensitivities to stressors. While early development stages during which organ systems are forming are more likely to be influenced by environmental factors, epigenetic studies should consider the full life cycle of an organism to avoid excluding any key biological end points later in the life cycle.…”

Molecular and tissue alterations of collagens in fibrosis

“…The DNA methyl-transferase (DNMT) family is responsible for DNA methylation of promoters leading to down-regulation of gene expression. Deregulation of DNA methylation is associated with fibrosis [90][91][92]. Genome-wide analysis of DNA methylation in liver shows hypomethylation of fibrogenic genes in a CCl4 murine model of fibrosis [93], and during the activation process of hepatic stellate cells (HSC) [94].…”