The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6.
Cell Stem Cell. 2012 Sep 7;11(3):333-45. doi: 10.1016/j.stem.2012.07.001. Epub 2012 Aug 2.
In skeletal muscle, asymmetrically dividing satellite stem cells give rise to committed satellite cells that transcribe the myogenic determination factor Myf5, a Pax7-target gene. We identified the arginine methyltransferase Carm1 as a Pax7 interacting protein and found that Carm1 specifically methylates multiple arginines in the N terminus of Pax7. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 resulting in the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3K4 methyltransferase complex to regulatory enhancers and the proximal promoter of Myf5. Finally, Carm1 is required for the induction of de novo Myf5 transcription following asymmetric satellite stem cell divisions. We defined the C-terminal MLL region as a reader domain for the recognition of arginine methylated proteins such as Pax7. Thus, arginine methylation of Pax7 by Carm1 functions as a molecular switch controlling the epigenetic induction of Myf5 during satellite stem cell asymmetric division and entry into the myogenic program.
在骨骼肌中，不对称分裂的卫星干细胞产生了定向的卫星干细胞，这些细胞转录肌生成决定因子 Myf5，这是 Pax7 的靶基因。我们鉴定出精氨酸甲基转移酶 Carm1 是 Pax7 的相互作用蛋白，并发现 Carm1 特异性地甲基化 Pax7 N 端的多个精氨酸。甲基化的 Pax7 直接结合 trithorax 蛋白 MLL1/2 的 C 端裂解形式，导致 ASH2L:MLL1/2:WDR5:RBBP5 组蛋白 H3K4 甲基转移酶复合物被招募到调控增强子和 Myf5 的近端启动子。最后，Carm1 是不对称卫星干细胞分裂后诱导新的 Myf5 转录所必需的。我们将 MLL 区的 C 端定义为识别精氨酸甲基化蛋白（如 Pax7）的读取域。因此，Carm1 对 Pax7 的精氨酸甲基化作为分子开关，控制卫星干细胞不对称分裂和进入肌生成程序时 Myf5 的表观遗传诱导。
