Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis
Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis
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DOI：
10.15252/embr.201540159
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发表时间：
2015-08-01
期刊：
影响因子：
7.7
通讯作者：
Puri, Pier Lorenzo
中科院分区：
文献类型：
--
作者：
Albini, Sonia;Toto, Paula Coutinho;Puri, Pier Lorenzo
虽然SWI/SNF染色质重塑复合体的两个催化亚基-Brahma(BRM)和BRG1-几乎总是共表达的，但它们相互排斥地结合到不同的SWI/SNF复合体中表明，基于BRG1和BRM的SWI/SNF复合体执行特定的功能。在这里，我们表明BRG1和BRM在肌肉分化的不同阶段具有不同的功能。在分化的早期阶段，BRG1是激活肌肉基因转录所必需的，而BRM是在肌肉基因激活之前抑制Ccnd1和细胞周期停滞所必需的。在BRM缺陷的成肌细胞中，CCND1基因敲除挽救了退出细胞周期的能力，但不能恢复终末分化，揭示了BRM在激活晚期肌肉基因表达方面的先前未知的作用，而不依赖于细胞周期的控制。一直以来，BRM基因缺失的小鼠在损伤后表现出肌肉再生受损，伴随着卫星细胞的异常增殖和新肌纤维的延迟形成。这些数据揭示了BRM通过形成抑制性和激活性SWI/SNF复合体在骨骼肌发生过程中的阶段特异性作用。
Although the two catalytic subunits of the SWI/SNF chromatin-remodeling complex-Brahma (Brm) and Brg1-are almost invariably co-expressed, their mutually exclusive incorporation into distinct SWI/SNF complexes predicts that Brg1-and Brm-based SWI/SNF complexes execute specific functions. Here, we show that Brg1 and Brm have distinct functions at discrete stages of muscle differentiation. While Brg1 is required for the activation of muscle gene transcription at early stages of differentiation, Brm is required for Ccnd1 repression and cell cycle arrest prior to the activation of muscle genes. Ccnd1 knockdown rescues the ability to exit the cell cycle in Brm-deficient myoblasts, but does not recover terminal differentiation, revealing a previously unrecognized role of Brm in the activation of late muscle gene expression independent from the control of cell cycle. Consistently, Brm null mice displayed impaired muscle regeneration after injury, with aberrant proliferation of satellite cells and delayed formation of new myofibers. These data reveal stage-specific roles of Brm during skeletal myogenesis, via formation of repressive and activatory SWI/SNF complexes.