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Mechanisms that Couple Chromatin Modifications to Transcription

将染色质修饰与转录结合起来的机制

基本信息

批准号：
10618263
负责人：
KAREN M ARNDT
金额：
$ 46.27万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

项目摘要

Project Summary The goal of this research program is to elucidate the proteins and mechanisms that regulate transcription within the context of chromatin, a process critical to every eukaryotic cell. Nucleosomes pose barriers to RNA polymerase II (Pol II) that must be overcome for accurate and efficient gene expression, and whose properties and interactions are modulated by post-translational modification. During transcription elongation, a conserved set of factors assembles with Pol II and facilitates its transit by altering the stability, positioning, and post- translational modification states of nucleosomes. The proposal addresses three major challenges related to these functions of eukaryotic transcription elongation factors. (1) What are the mechanisms by which transcription elongation factors couple chromatin changes, including histone modifications, to RNA synthesis? (2) How are the patterns of these epigenetic modifications determined? (3) What are the primary versus indirect functions of core components of the Pol II elongation machinery? These questions will be approached through a comprehensive analysis of the Paf1 complex (Paf1C) and proteins with which it interacts. Paf1C is a highly conserved transcription elongation factor that globally associates with Pol II on the bodies of active genes. The multifunctional nature of Paf1C affords a unique opportunity to reveal how transcription is coupled to co-transcriptional events. To this end, a multifaceted approach comprising innovative genetic and proteomic screens, mechanistic biochemistry, and genomics will be deployed. This project will determine how Paf1C stimulates critical histone modifications and interfaces with a chromatin remodeling factor with genetic links to prostate cancer. In-depth studies of the interactions between Paf1C and the Pol II elongation complex will uncover the molecular mechanisms that spatially constrain Paf1C-dependent chromatin changes to active genes. Finally, the primary and subunit-specific functions of Paf1C, as well as the cellular pathways that compensate for its absence, will be determined. The studies will be performed in Saccharomyces cerevisiae to capitalize on the sophisticated tools developed for that system. Given the strong conservation of all proteins and histone modifications studied, the conceptual advances that arise from this work will have direct implications for the understanding of gene regulation in humans, where defects in this process cause a wide range of cancers and other diseases.

项目摘要这个研究项目的目标是阐明调节转录的蛋白质和机制在染色质的背景下，这是一个对每个真核细胞都至关重要的过程。核小体对RNA构成屏障聚合酶II（Pol II），必须克服它才能准确有效地表达基因，及其特性并且相互作用通过翻译后修饰来调节。在转录延伸过程中，一系列因素与Pol II组装在一起，并通过改变稳定性，定位和后核小体的翻译修饰状态。该提案涉及三个主要挑战，真核生物转录延伸因子的这些功能。(1)是什么机制转录延伸因子偶联染色质变化，包括组蛋白修饰，RNA合成？ (2)这些表观遗传修饰的模式是如何确定的？(3)什么是主要与 Pol II延伸机械核心部件的间接功能？这些问题将在通过对Paf 1复合物（Paf 1C）及其相互作用的蛋白质的全面分析。Paf1C是一个一种高度保守的转录延伸因子，在活性细胞体上与Pol II全面相关基因. Paf1C的多功能性质提供了一个独特的机会来揭示转录是如何耦合的到共同转录事件。为此，一个多方面的方法，包括创新的遗传和蛋白质组学屏幕，机械生物化学和基因组学将被部署。该项目将确定Paf1C如何刺激关键的组蛋白修饰，并与染色质重塑因子相互作用，前列腺癌深入研究Paf1C和Pol II延伸复合物之间的相互作用，揭示了在空间上限制Paf1C依赖性染色质变化的分子机制，基因.最后，Paf1C的主要和亚单位特异性功能，以及细胞途径，如果没有，将被淘汰。研究将在酿酒酵母中进行，利用为该系统开发的复杂工具。考虑到所有蛋白质的高度保守性和组蛋白修饰的研究，从这项工作中产生的概念上的进步将有直接的对理解人类基因调控的影响，该过程中的缺陷会导致广泛的一系列癌症和其他疾病。