ROLE OF CHROMATIN REMODELING IN MUSCLE DEVELOPMENT

染色质在很大程度上是转录机器无法接触到的。SWI/SNF是一种进化上保守的多蛋白复合体，可以通过依赖于ATP的方式改变染色质结构，促进体外转录因子的结合。虽然哺乳动物的SWI/SNF亚基参与了转录调控、细胞分裂、分化和发育，但哺乳动物SWI/SNF调控的基因在体内尚未被发现。初步证据表明，哺乳动物SWI/SNF通过激活两个肌肉特异性基因--肌肉生成素和肌球蛋白重链的转录而参与肌肉发生。这一建议的具体目的是：1)确定由于SWI/SNF具有改变染色质结构和/或促进转录因子结合的能力，是否需要SWI/SNF来进行肌生成素基因的转录。2)确定是否需要SWI/SNF来维持肌肉分化。3)研究SWI/SNF在肌肉肌酸激酶(MCK)增强子调控中的作用。这项工作将描述SWI/SNF在体内的功能，并增加我们对染色质结构变化如何在正常发育过程和癌症中抑制和去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.