Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle

Abstract

MyoD is a master regulator of the skeletal muscle gene expression program. ChIP-Seq analysis has recently revealed that MyoD binds to a large number of genomic loci in differentiating myoblasts, yet only activates transcription at a subset of these genes. Here we discuss recent data suggesting that the ability of MyoD to mediate gene expression is regulated through the function of Polycomb and Trithorax Group proteins. Based on studies of the muscle-specific myog gene, we propose a model where the transcriptional activators Mef2d and Six4 mediate recruitment of Trithorax Group proteins Ash2L/MLL2 and UTX to MyoD-bound promoters to overcome the Polycomb-mediated repression of muscle genes. Modulation of the interaction between Ash2L/MLL2 and Mef2d by the p38α MAPK signaling pathway in turns provides fine-tuning of the muscle-specific gene expression program. Thus Mef2d, Six4, and p38α MAPK function coordinately as regulators of a master regulator to mediate expression of MyoD target genes.

Figure 1

Model for the coordinate activation of PcG-repressed muscle genes. (A) The transcriptional repressor YY1 targets Ezh2 to muscle-specific genes, establishing the repressive H3K27me3 mark across the locus. (B) MyoD binding at the promoter, in conjunction with Mef2d and Six4, establishes a transcriptionally poised promoter characterized by a localized demethylation of H3K27me3 (limited to the promoter) and the presence of acetylated histones. However, transcriptional competency is not achieved due to the presence of repressive H3K27me3 mark within the gene. (C) Phosphorylation of Mef2d by p38 MAPK allows the recruitment of Ash2L/MLL2 complex leading to H3K4me3 within the gene. (D) Phosphorylation of the CTD of RNA Pol II allows the transfer of UTX onto the elongating polymerase to mediate demethylation into the gene, permitting muscle-specific gene expression. See text for further details.