Paper of the Month - June 2015

Wales S, Hashemi S, Blais A, McDermott JC. Global MEF2 target gene analysis in cardiac and skeletal muscle reveals novel regulation of DUSP6 by p38MAPK-MEF2 signaling. Nucleic Acids Res. 2014 Oct;42(18):11349-62.

­­The goal of our lab is to understand the role of transcription factor MEF2 during development and disease. MEF2 (A-D) is expressed in a wide array of tissues and can regulate the expression of tissue-specific genes. Skeletal and cardiac muscle are referred to as striated muscle and depend on sarcomeres for contraction. MEF2 is expressed in both of these tissues and controls the expression of several shared target genes related to two fundamental processes in striated muscle: contraction and metabolism. Based on this it may be possible for MEF2 to regulate other critical aspects of skeletal and cardiac muscle function, yet a thorough comparison of MEF2 target genes in these two cell types has not been done. We utilized ChIP-seq to identify MEF2A target genes in C2C12 and primary cardiomyocytes to determine the shared and distinct patterns of MEF2-dependent regulation in these cell types. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. The pattern of MEF2 binding within the genome (promoter, inter- and intra-genic regions), neighbouring consensus sequences, (e.g. AP-1), and enriched GO terms (e.g. actin cytoskeleton) were highly similar in both cells types. Using siRNA mediated gene silencing of MEF2A we validated the MEF2-dependent regulation of a subset of these genes. In particular we showed that Dusp6, a MAPK phosphatase, is differentially regulated by MEF2A and MEF2D in a p38MAPK-dependent manner. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages.

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