Transcription Factor Function in Chromatin

描述（由申请人提供）：为了理解正常发育和分化，有必要确定细胞启动新的基因表达程序并促进特定细胞谱系形成的机制。通常，这涉及转录沉默的基因的激活，并且可以并入抑制性染色质结构中。证据支持这样的想法，即分化特异性转录调节因子和重塑染色质结构的酶合作，使基因组DNA更容易进入转录机制。SWI/SNF酶以ATP依赖的方式改变核小体结构，并促进体外和体内转录因子的功能。这些酶的成分是胚胎发育所必需的，有些还起到肿瘤抑制剂的作用。此外，SWI/SNF酶与其他已知的肿瘤抑制剂相互作用，并参与细胞周期控制。因此，这些酶是广泛需要正常的细胞功能和他们的失调是牵连在肿瘤formation.We最近证明了需要SWI/SNF酶在骨骼肌和脂肪细胞分化的启动。骨骼肌分化长期以来一直是研究分化基本原理的模型。在分子水平上了解骨骼肌分化将对研究肌肉再生和横纹肌肉瘤（肌源性肿瘤）的形成具有重要意义。脂肪细胞是哺乳动物能量平衡系统的核心组成部分。它们在营养丰富的时期储存甘油三酯，在热量缺乏的时期释放游离脂肪酸。在人类中，脂肪细胞组织的过度发育或肥胖影响了美国30%的成年人。这一人群患非胰岛素依赖型糖尿病、冠状动脉疾病和高血压的风险显著增加。因此，启动和调节脂肪细胞分化的分子事件的表征也是一个重要的医学问题。目的1和2的目标是了解SWI/SNF染色质重塑酶促进发育和分化的机制，重点是SWI/SNF酶和关键转录调控因子如何启动新的基因表达程序。目的3将探讨SWI/SNF酶在不同分化途径和胚胎发生中的通用性。

DESCRIPTION (provided by applicant): To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that may be incorporated into repressive chromatin structure. Evidence supports the idea that differentiation specific transcriptional regulators and enzymes that remodel chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. SWI/SNF enzymes alter nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some act as tumor suppressors. Additionally, SWI/SNF enzymes interact with other known tumor suppressors and are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and their misregulation is implicated in tumor formation.We recently demonstrated a requirement for SWI/SNF enzymes in the initiation of skeletal muscle and adipocyte differentiation. Skeletal muscle differentiation has long been a model for studying fundamental principles of differentiation. Understanding skeletal muscle differentiation at a molecular level will have significant implications for investigating muscle regeneration and the formation of rhabdomyosarcomas, which are tumors of myogenic derivation. Adipocytes are a central component of the energy balance system in mammals. They store triglycerides during periods of nutritional abundance and release free fatty acids during periods of caloric deficiency. In humans, excessive development of adipocyte tissue, or obesity, affects 30 percent of the adults in the U.S. This population is at significantly increased risk for non-insulin dependent diabetes, coronary artery disease, and hypertension. Characterization of the molecular events that initiate and regulate adipocyte differentiation is therefore also an important medical concern. The goals of Aims 1 and 2 are to understand the mechanisms by which SWI/SNF chromatin remodeling enzymes promote development and differentiation, with emphasis on how SWI/SNF enzymes and key transcriptional regulators initiate new programs of gene expression. Aim 3 will probe the generality of the requirement for SWI/SNF enzymes in different differentiation pathways and embryogenesis.