Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38γ/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy.

中文翻译：

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抗肌萎缩蛋白糖蛋白复合物调节肌肉干细胞承诺的表观遗传激活。

骨骼肌中不对称分裂的肌肉干细胞产生定型细胞，其中成肌决定因子Myf5被Pax7转录激活。这种激活依赖于Carm1，后者使多个精氨酸残基上的Pax7甲基化，从而将ASH2L：MLL1 / 2：WDR5：RBBP5组蛋白甲基转移酶复合物募集到Myf5的近端启动子上。在这里，我们发现Carm1是p38γ/ MAPK12的特定底物，并且Carm1的磷酸化阻止了它的核易位。肌肉干细胞中p38γ/ p-Carm1复合物的基础定位是通过β1-syntrophin与肌营养不良蛋白-糖蛋白复合物（DGC）结合而发生的。在肌营养不良蛋白缺乏的肌肉干细胞进行不对称分裂时，p38γ/β1-syntrophin相互作用被消除，导致Carm1磷酸化增强。生成的祖细胞显示出减少的Carm1与Pax7的结合，减少的染色质的H3K4-甲基化，以及减少的Myf5和其他Pax7靶基因的转录。因此，我们的实验表明，p38γ/ Carm1的失调导致Duchenne肌营养不良症的表观遗传基因调控改变。