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Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation

机译:组蛋白脱乙酰基酶的信号依赖性核输出调节肌肉分化

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Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors associate with myogenic basic helix-loop-helix transcription factors such as MyoD to activate skeletal myogenesis. MEF2 proteins also interact with the class Ⅱ histone deacetylases HDAC4 and HDAC5, resulting in repression of MEF2-dependent genes. Execution of the muscle differentiation program requires release of MEF2 from repression by HDACs, which are expressed constitutively in myoblasts and myotubes. Here we show that HDAC5 shuttles from the nucleus to the cytoplasm when myoblasts are triggered to differentiate. Calcium/ calmodulin-dependent protein kinase (CaMK) signalling, which stimulates myogenesis and prevents formation of MEF2-HDAC complexes, also induces nuclear export of HDAC4 and HDAC5 by phosphorylation of these transcriptional repressors. An HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and acts as a dominant inhibitor of skeletal myogenesis, whereas a cytoplasmic HDAC5 mutant is unable to block efficiently the muscle differentiation program. Our results highlight a mechanism for transcriptional regulation through signal- and differentiation-dependent nuclear export of a chromatin-remodelling enzyme, and suggest that nucleo-cyto-plasmic trafficking of HDACs is involved in the control of cellular differentiation.
机译:肌细胞增强因子2(MEF2)家族的转录因子成员与成肌基本螺旋-环-螺旋转录因子(如MyoD)相关联,以激活骨骼肌新生。 MEF2蛋白还与Ⅱ类组蛋白脱乙酰基酶HDAC4和HDAC5相互作用,导致MEF2依赖基因的抑制。肌肉分化程序的执行需要通过HDAC释放MEF2,HDAC在成肌细胞和肌管中组成性表达。在这里,我们显示当成肌细胞被触发分化时,HDAC5从细胞核穿梭到细胞质。钙/钙调蛋白依赖性蛋白激酶(CaMK)信号,刺激肌发生并阻止MEF2-HDAC复合物的形成,还通过这些转录阻遏物的磷酸化诱导HDAC4和HDAC5的核输出。缺少两个CaMK磷酸化位点的HDAC5突变体对CaMK介导的核输出有抗性,并作为骨骼肌生成的主要抑制剂,而胞质HDAC5突变体则无法有效地阻止肌肉分化程序。我们的研究结果突出了通过信号和分化依赖的染色质重塑酶的核出口的转录调控机制,并建议HDACs的核细胞质运输涉及细胞分化的控制。

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