Mechanisms of Transcription Factor Yin Yang 1

描述（由申请人提供）：序列特异性DNA结合转录因子在许多发育过程和细胞行为控制中起关键作用。Yin Yang 1（YY 1）是一个由41个氨基酸组成的Kruppel相关锌指转录因子，与位于许多细胞和病毒基因启动子和增强子中的CGCCATNTT共有DNA元件结合。像许多转录因子一样，YY 1需要辅激活子和辅阻遏子才能正常发挥作用。有趣的是，YY 1似乎是同样有效的激活剂和阻遏物取决于其相对浓度，其结合伙伴，并启动子上下文。虽然YY 1调控的基因数量不断增加，但该因子调控转录的确切机制仍不清楚。这项提案的长期目标是对YY 1如何调节转录有更深入的了解。先前的研究表明，YY 1与组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）相互作用。目前提出的研究重点是详细分析YY 1-HAT和YY 1-HDAC相互作用的功能意义。待探索的假设是，YY 1的至少一些作用是其与HAT和HDAC接触的结果，这允许HAT或HDAC的募集以酶促修饰组蛋白并因此影响转录。将检查一种替代的、非互斥的假设，其中HAT或HDAC与YY 1之间的相互作用改变YY 1的乙酰化状态，从而改变YY 1的活性。最后，将严格鉴定和表征在体内由YY 1与HAT或HDAC组合调节的基因。 考虑到YY 1可能控制的基因的长列表，毫无疑问，这个因子为转录调控的研究提供了一个有吸引力的模型，并且通过彻底了解YY 1的活性是如何调节的，可以获得巨大的好处。这些研究不仅将从根本上有助于更好地理解基因调控的分子生物学，而且还将提供关于精确控制许多生理学上重要的基因的重要见解。

DESCRIPTION (provided by applicant): Sequence-specific DNA-binding transcription factors play pivotal roles in many developmental processes and in the control of cell behavior. Yin Yang 1 (YY1) is a 41 4-amino-acid Kruppel-related zinc finger transcription factor that binds to the CGCCATNTT consensus DNA element located in promoters and enhancers of many cellular and viral genes. Like many transcription factors, YY1 requires coactivators and corepressors to function properly. Interestingly, YY1 appears to be equally effective as an activator and as a repressor depending on its relative concentration, its binding partners, and on promoter context. Although reports of the number of genes that might be regulated by YY1 are ever increasing, the exact mechanisms by which this factor regulates transcription are still unclear. The long-term goal of this proposal is aimed at obtaining a greater mechanistic understanding of how YY1 regulates transcription. Previous studies indicate that YY1 interacts with histone acetyltransferases (HATs) and with histone deacetylases (HDACs). The current proposed study focuses on a detailed analysis of the functional significance of the YY1-HATs and YY1-HDACs interactions. The hypothesis to be explored is that at least some of the effects of YY1 are a result of its contact with HATs and with HDACs, which allows the recruitment of HATs or HDACs to enzymatically modify histones and consequently affect transcription. An alternative, non-mutually exclusive hypothesis will be examined in which the interaction between HATs or HDACs and YY1 modifies the acetylation status of YY1 and consequently alters YY1s activity. Finally, genes that are regulated by YY1 in combination with HATs or HDACs in vivo will be rigorously identified and characterized. Given the long list of genes that could potentially be controlled by YY1, there is no dispute that this factor provides an attractive model for the study of transcriptional regulation and that enormous benefits can be gained by thoroughly understanding how the activity of YY1 is regulated. These studies will not only contribute fundamentally to a better understanding of the molecular biology of gene regulation but will also provide critical insights regarding the precise control of many physiologically important genes.