Wales Stephanie, Hashemi Sara, Blais Alexandre, McDermott John C
Department of Biology, York University, 4700 Keele Street Toronto, Ontario, M3J 1P3 Canada Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research on Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada.
Ottawa Institute of Systems Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, Ontario, K1H 8M5 Canada.
Nucleic Acids Res. 2014 Oct;42(18):11349-62. doi: 10.1093/nar/gku813. Epub 2014 Sep 12.
MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of cardiomyocytes and skeletal myoblasts. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. Genomic targets were compared to differentially expressed genes in RNA-seq analysis of MEF2A depleted myogenic cells, revealing two prominent genetic networks. Genes largely associated with muscle development were down-regulated by loss of MEF2A while up-regulated genes reveal a previously unrecognized function of MEF2A in suppressing growth/proliferative genes. Several up-regulated (Tprg, Mctp2, Kitl, Prrx1, Dusp6) and down-regulated (Atp1a2, Hspb7, Tmem182, Sorbs2, Lmod3) MEF2A target genes were chosen for further investigation. Interestingly, siRNA targeting of the MEF2A/D heterodimer revealed a somewhat divergent role in the regulation of Dusp6, a MAPK phosphatase, in cardiac and skeletal myogenic lineages. Furthermore, MEF2D functions as a p38MAPK-dependent repressor of Dusp6 in myoblasts. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages.
MEF2在心肌和骨骼肌谱系的转录调控中发挥着重要作用。为了确定MEF2A基因组的重叠和独特靶点，我们利用了心肌细胞和成骨骼肌细胞的ChIP-exo分析。在成骨骼肌细胞和心肌细胞中分别有2783个和1648个MEF2A结合峰，共鉴定出294个共同结合位点。将基因组靶点与MEF2A缺失的成肌细胞RNA-seq分析中的差异表达基因进行比较，揭示了两个主要的基因网络。MEF2A缺失导致与肌肉发育密切相关的基因下调，而上调基因揭示了MEF2A在抑制生长/增殖基因方面以前未被认识的功能。选择了几个上调（Tprg、Mctp2、Kitl、Prrx1、Dusp6）和下调（Atp1a2、Hspb7、Tmem182、Sorbs2、Lmod3）的MEF2A靶基因进行进一步研究。有趣的是，针对MEF2A/D异二聚体的siRNA在心脏和骨骼肌成肌谱系中对丝裂原活化蛋白激酶磷酸酶Dusp6的调控中显示出某种程度的不同作用。此外，在成肌细胞中，MEF2D作为Dusp6的p38丝裂原活化蛋白激酶依赖性阻遏物发挥作用。这些数据表明，MEF2在骨骼肌和心肌谱系中协调信号依赖性基因表达的共同和非重叠程序。
