Essential Role of MeCP2 in the Regulation of Myofibroblast Differentiation during Pulmonary Fibrosis

Abstract

DNA methylation is a key mechanism for repression of gene expression, including that of ␣-smooth muscle actin (␣-SMA) gene expression in fibroblasts. However, the trans-acting factors that interact with the methylated ␣-SMA gene to regulate its expression have not been identified. Using gel shift and chromatin immunoprecipitation (ChIP) assays, methyl CpG binding protein 2 (MeCP2) was shown to bind to the ␣-SMA gene. Suppression of MeCP2 gene expression by siRNA or its deficiency in lung fibroblasts isolated from MeCP2 knockout mice caused significant reduction of ␣-SMA gene expression. In contrast, transient transfection of MeCP2 expression plasmid into fibroblasts enhanced ␣-SMA gene expression. Moreover, in vivo studies revealed that compared to their wild type littermates, MeCP2-deficient mice exhibited significantly decreased alveolar wall thickness, inflammatory cell infiltration, interstitial collagen deposition, and myofibroblast differentiation in response to endotracheal injection of bleomycin. Thus, MeCP2 is essential for myofibroblast differentiation and pulmonary fibrosis.

DNA methylation in fibrosis

“…The same study also found that mice deficient in MeCP2 showed lesser levels of fibrosis when treated with bleomycin than was seen in the wild-type (Hu et al, 2011). In systemic sclerosis we have also seen elevated levels of MeCP2 in fibroblasts .…”

“…This indicates that MeCP2 acts as an activator of α-SMA expression. However, it was also found methylation of the α-SMA promoter region inhibited the stimulatory effect of MeCP2 (Hu et al, 2011).…”

Epigenetics within the matrix

“…Suppression of MeCP2 expression in pulmonary fibroblasts increases αSMA expression which is a classical feature of myofibroblast differentiation. 26 Furthermore, in a bleomycin-induced pulmonary fibrosis model MeCP2 -/-displayed decreased pulmonary collagen deposition and decreased myofibroblast differentiation compared with wild type animals. 26 While MeCP2 can bind to unmethylated DNA, it is well recognized that it preferentially binds to methylated DNA to assist and promote chromatin remodeling.…”

“…26 Furthermore, in a bleomycin-induced pulmonary fibrosis model MeCP2 -/-displayed decreased pulmonary collagen deposition and decreased myofibroblast differentiation compared with wild type animals. 26 While MeCP2 can bind to unmethylated DNA, it is well recognized that it preferentially binds to methylated DNA to assist and promote chromatin remodeling. 27 Thus, several independent studies linking MeCP2 to myofibroblast differentiation all implicate alterations in DNA methylation at the heart of this process.…”

Epigenetics in Liver Disease

“…MeCP2 may be a generic core-regulator of tissue fibrosis since mecp2-deleted mice are also protected from pulmonary fibrosis. 38 MeCP2 operates two concurrent mechanisms to ensure epigenetic silencing of PPARc and HSC transdifferentiation. MeCP2 directly binds to methylCpG-rich regulatory regions in the PPARc promoter and recruits H3K9me3-modifying enzymes that suppress transcription initiation.…”