p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci
p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci
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DOI：
10.1038/ng1378
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发表时间：
2004-07-01
期刊：
影响因子：
30.8
通讯作者：
Puri, PL
中科院分区：
文献类型：
--
作者：
Simone, C;Forcales, SV;Puri, PL
在骨骼肌形成过程中，通过向肌肉特异性位点招募染色质修饰酶来实现基因组向末端分化的重编程（1,2）。细胞外信号级联在靶向这些酶的单个基因中的相对作用尚不清楚。在这里，我们发现分化激活的p38通路（3-5）将SWI-SNF染色质重塑复合体靶向到肌源性位点。分化后，p38激酶被招募到肌肉调节元件的染色质上。阻断p38 α / β通过阻止这些元件上的SWI-SNF复合物的募集来抑制肌肉基因的转录，而不影响肌肉调节因子和乙酰转移酶的染色质结合。SWI-SNF亚基BAF60可以在体外被p38 α - β磷酸化，并通过表达组成活性MKK6在成肌细胞中强制激活p38 α / β（参考文献）。5-7)促进了计划外的SWI-SNF向肌生成素启动子的募集。相反，SWI-SNF酶亚基的失活取消了mkk6依赖性肌肉基因表达的诱导。这些结果确定了分化激活的p38的一个意想不到的功能，通过选择性地靶向肌肉调节元件的SWI-SNF，将外部线索转化为离散位点上的染色质修饰。
During skeletal myogenesis, genomic reprogramming toward terminal differentiation is achieved by recruiting chromatin-modifying enzymes to muscle-specific loci(1,2). The relative contribution of extracellular signaling cascades in targeting these enzymes to individual genes is unknown. Here we show that the differentiation-activated p38 pathway(3-5) targets the SWI-SNF chromatin-remodeling complex to myogenic loci. Upon differentiation, p38 kinases were recruited to the chromatin of muscle-regulatory elements. Blockade of p38alpha/beta repressed the transcription of muscle genes by preventing recruitment of the SWI-SNF complex at these elements without affecting chromatin binding of muscle-regulatory factors and acetyltransferases. The SWI-SNF subunit BAF60 could be phosphorylated by p38alpha-beta in vitro, and forced activation of p38alpha/beta in myoblasts by expression of a constitutively active MKK6 (refs. 5-7) promoted unscheduled SWI-SNF recruitment to the myogenin promoter. Conversely, inactivation of SWI-SNF enzymatic subunits abrogated MKK6-dependent induction of muscle gene expression. These results identify an unexpected function of differentiation-activated p38 in converting external cues into chromatin modifications at discrete loci, by selectively targeting SWI-SNF to muscle-regulatory elements.