Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372. Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2. Our results indicate that signal-dependent degradation of EZH2 is a prerequisite for satellite cells differentiation and identify PJA1 as a new player in the epigenetic control of muscle gene expression.

译文

:Polycomb蛋白是重要的染色质修饰剂,可通过转录抑制调节干细胞分化。在骨骼肌祖细胞中,zeste同源物2(EZH2)的增强子是Polycomb Repressive Complex 2(PRC2)的催化亚基,有助于将肌肉基因的染色质维持在抑制状态,而其下调则允许通过成肌程序进行。在这里,我们显示p38α激酶通过苏氨酸372的磷酸化促进分化肌肉细胞中的EZH2降解。生化和遗传证据表明,MYOD诱导的E3泛素连接酶Praja1(PJA1)在p38α激活后参与调节EZH2的水平。 EZH2在增殖的成肌细胞中过早降解被低水平的PJA1,其细胞质定位和对未磷酸化EZH2的较低活性所阻止。我们的结果表明,EZH2的信号依赖性降解是卫星细胞分化的先决条件,并确定PJA1是肌肉基因表达的表观遗传控制中的新角色。

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