ROLE OF CHROMATIN REMODELING IN GROWTH CONTROL

染色质重塑在生长控制中的作用

• 批准号: 6027585
• 负责人: GAVIN R SCHNITZLER
• 金额: $ 9.96万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6027585
• 关键词: Xenopus oocyte; amidohydrolases; cell growth regulation; chromatin; electron microscopy; enzyme activity; genetic transcription; nucleic acid metabolism; nucleic acid structure; nucleosomes; retinoblastoma protein; transcription factor

The state of chromatin at any given gene is a critical aspect of its regulation. Chromatin establishes a repressive environment that is inhibitory to transcription, from prevention of initial factor binding to inhibition of elongation. This repressive effect appears to be relieved by ATP-dependent chromatin remodeling complexes and enzymes that acetylate the histone tails, and enhanced by complexes of repressor proteins, histone deacetylases, and other factors. Recent evidence suggests that two chromatin remodeling complexes, hSWI/SNF and NRD, might be essential for growth control mechanisms through recruitment by the retinoblastoma family of tumor suppressor proteins. Although this evidence indicates an important role for these complexes, it tells us very little about their mechanism of action. Current evidence, from my work and others', suggest potential mechanisms by which remodeling complexes could activate, as well as repress, transcription. The purpose of the research described here is to analyze the mechanisms of the two human chromatin remodeling complexes, hSWI/SNF and NRD, to better understand their potential effects on transcriptional control. These complexes will be assayed for their ability to affect nucleosome mobility and higher-order structures, and for their effects to be influenced by transcription factors and chromatinassociated proteins. The role of chromatin remodeling in facilitating the second function of NRD, histone deacetylation will also be examined. The ability of the retinoblastoma protein to interact with these complexes to recruit them to promoters will be examined in vitro and in vivo, with the aim of establishing a strong model system for examining the role of chromatin remodeling in growth control decisions and general transcriptional regulation.

染色质在任何给定基因上的状态是其调控的一个关键方面。染色质建立了一种抑制转录的环境，从阻止起始因子结合到抑制延伸。这种抑制作用似乎被依赖于ATP的染色质重塑复合体和乙酰化组蛋白尾部的酶所缓解，并被阻遏蛋白、组蛋白去乙酰化酶和其他因子的复合体所增强。最近的证据表明，两个染色质重塑复合体，hSWI/SNF和NRD，可能通过被肿瘤抑制蛋白家族的视网膜母细胞瘤家族招募而在生长控制机制中发挥重要作用。尽管这一证据表明了这些复合体的重要作用，但它告诉我们的关于它们的作用机制却很少。来自我和其他人的工作的现有证据表明，重塑复合体可以激活和抑制转录的潜在机制。本研究的目的是分析hSWI/SNF和NRD这两个人类染色质重塑复合体的机制，以更好地了解它们在转录调控中的潜在作用。这些复合体将被检测它们影响核小体移动和高阶结构的能力，以及它们的效应是否受到转录因子和染色质相关蛋白的影响。染色质重塑在促进NRD的第二功能，组蛋白去乙酰化中的作用也将被研究。视网膜母细胞瘤蛋白与这些复合体相互作用以招募它们成为启动子的能力将在体外和体内进行检测，目的是建立一个强大的模型系统，用于研究染色质重塑在生长控制决策和一般转录调控中的作用。