ROLE OF CHROMATIN REMODELING IN MUSCLE DEVELOPMENT

染色质在很大程度上是转录机制无法接近的。SWI/SNF是一种进化上保守的多蛋白复合物，能够以ATP依赖的方式修饰染色质结构，并促进体外转录因子的结合。尽管哺乳动物SWI/SNF亚基与转录控制、细胞分裂、分化和发育有关，但哺乳动物SWI/SNF调控的基因尚未在体内鉴定。初步证据表明，哺乳动物SWI/SNF通过激活肌原蛋白（myogenin）和肌球蛋白重链（myosin heavy chain）两个肌肉特异性基因的转录参与肌肉发生。本提案的具体目的是：1)确定由于SWI/SNF改变染色质结构和/或促进转录因子结合的能力，是否需要肌原蛋白基因转录。2)确定是否需要SWI/SNF维持肌肉分化。3)研究SWI/SNF在肌肉肌酸激酶（MCK）增强子调控中的作用。这项工作将表征SWI/SNF在体内的功能，并增加我们对染色质结构改变如何在正常发育过程和癌症中抑制和抑制染色质结构的理解。

Chromatin is largely inaccessible to the transcriptional machinery. SWI/SNF is an evolutionarily conserved multiprotein complex that can modify chromatin structure in an ATP dependent manner and facilitate transcription factor binding in vitro. Although mammalian SWI/SNF subunits have been implicated in transcriptional control, cell division, differentiation and development, the genes regulated by mammalian SWI/SNF have not yet been identified in vivo. Preliminary evidence shows that mammalian SWI/SNF participates in myogenesis by activating transcription of two muscle specific genes, myogenin and myosin heavy chain. The specific aims of this proposal are to: 1) determine whether SWI/SNF is required for myogenin gene transcription due to its ability to alter chromatin structure and/or facilitate transcription factor binding. 2) determine whether SWI/SNF is needed for maintenance of muscle differentiation. 3) examine how SWI/SNF functions in the regulation of the muscle creatine kinase (MCK) enhancer. This work will characterize SWI/SNF function in vivo and increase our understanding of how alterations in chromatin structure serve to repress and derepress chromatin structure in both normal developmental processes and in cancer.