Transcription Factor Function in Chromatin

描述(申请人提供)：为了了解正常的发育和分化，有必要确定细胞启动新的基因表达程序并促进特定细胞系形成的机制。通常，这涉及到转录沉默的基因的激活，这些基因可能被合并到抑制性染色质结构中。有证据支持这样的观点，即分化、特异的转录调节因子和重塑染色质结构的酶相互作用，使基因组DNA更容易进入转录机制。SWI/SNF酶以一种依赖于ATP的方式改变核小体结构，并在体外和体内促进转录因子的功能。这些酶的成分对胚胎发育是必不可少的，其中一些起到了肿瘤抑制的作用。此外，SWI/SNF酶与其他已知的肿瘤抑制因子相互作用，并与细胞周期控制有关。因此，这些酶是正常细胞功能广泛需要的，它们的错误调节与肿瘤的形成有关。我们最近证明了在骨骼肌和脂肪细胞分化的启动过程中需要SWI/SNF酶。长期以来，骨骼肌分化一直是研究分化的基本原理的模型。在分子水平上了解骨骼肌的分化对于研究肌肉再生和横纹肌肉瘤的形成具有重要意义，横纹肌肉瘤是肌源性肿瘤。脂肪细胞是哺乳动物能量平衡系统的中心组成部分。它们在营养丰富的时期储存甘油三酯，在热量不足的时期释放游离脂肪酸。在人类中，脂肪组织的过度发育或肥胖影响着美国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特征也是一个重要的医学问题。目标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酶和关键转录调节因子如何启动新的基因表达程序。目的3探讨不同分化途径和胚胎发育对SWI/SNF酶需求的共性。

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.