MLL1 is required for PAX7 expression and satellite cell self-renewal in mice
MLL1 is required for PAX7 expression and satellite cell self-renewal in mice
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DOI：
10.1038/s41467-019-12086-9
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发表时间：
2019-09-18
影响因子：
16.6
通讯作者：
Rudnicki, Michael A.
中科院分区：
文献类型：
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作者：
Addicks, Gregory C.;Brun, Caroline E.;Rudnicki, Michael A.
PAX7 是一种配对同源盒转录因子，它指定肌肉干细胞的生肌特性，并通过刺激增殖同时抑制分化来充当节点因子。我们之前发现 PAX7 招募 H3K4 甲基转移酶 MLL1/2 以表观遗传方式激活靶基因。在这里，我们报告，在缺乏 Mll1 的情况下，成肌细胞在 Pax7 和 Myf5 启动子处表现出 H3K4me3 减少，并且 Pax7 和 Myf5 表达减少。 Mill 缺陷的成肌细胞无法增殖，但保留其分化潜力，而 Mll2 的缺失则没有明显的影响。 PAX7 在定型 Mll1 cKO 成肌细胞中的重新表达恢复了 Myf5 启动子处的 H3K4me3 富集和 Myf5 表达。卫星细胞中 Mll1 的缺失会减少卫星细胞的增殖和自我更新，并显着损害骨骼肌再生。 Pax7 表达在静止卫星细胞中不受影响，但在卫星细胞激活后明显下调。因此，MLL1 是体内 PAX7 表达和卫星细胞功能所必需的。此外，定型成肌细胞中 Myf5 转录激活需要 PAX7，而不是 MLL1。
PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mill-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.