Essential role of Mecp2 in the regulation of myofibroblast differentiation

Abstract

DNA methylation is a key mechanism of gene expression and previous studies suggest it suppresses α‐smooth muscle actin (α‐SMA) gene expression during myofibroblast differentiation. However, the trans‐acting factors that interact with the methylated α‐SMA gene and regulate its expression, have not been identified. Using gel shift and ChIP assays, MeCP2 was shown to bind to the methylated α‐SMA gene. Suppression of MeCP2 gene expression by siRNA or its deficiency in MeCP2 knock out mice led to reduced α‐SMA gene expression in isolated lung fibroblasts. In contrast, transient transfection of MeCP2 expression plasmid into fibroblasts enhanced α‐SMA gene expression. Further studies indicated 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 upon endotracheal injection of bleomycin. Thus MeCP2 is essential in myofibroblast differentiation and pulmonary fibrosis.