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The Role of Yeast Mediator in Transcriptional Regulation

酵母介体在转录调控中的作用

基本信息

批准号：
8197648
负责人：
Lawrence Christopher Myers
金额：
$ 30.17万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197648
关键词：
Address Affect Alzheimer&apos s Disease Binding Biochemical Biochemical Genetics Cell physiology Cells Chromatin Chromatin Structure Communication Complex DNA Binding Data Defect Developmental Process Disease Eukaryota Eukaryotic Cell Event Frustration Gene Expression Genes Genetic Genetic Screening Genetic Techniques Genetic Transcription Genomics Goals Histones In Vitro Infection Knowledge Lead Link Malignant Neoplasms Marshal Mediator of activation protein Modeling Modification Molecular Mutation Nucleic Acids Nucleosomes Physiological Play Positioning Attribute Property Proteins Proteomics RNA Polymerase II Regulation Repression Research Research Project Grants Resources Role SAGA Saccharomyces cerevisiae Sickle Cell Anemia Signal Repression System Tail Testing Therapeutic Transcriptional Regulation Work Yeasts base design fungus gene repression genetic regulatory protein genome-wide histone modification in vivo meetings mutant novel programs promoter protein complex reconstitution research study yeast genetics yeast protein

项目摘要

Mediator is a global transcriptional co-regulatory protein complex that plays a central role in the activation and repression of RNA polymerase II transcribed genes. The highly conserved composition and function of Mediator, as well as the intricacies of its mechanism, make Saccharomyces cerevisiae an ideal model for incisive molecular studies. The current paradigm for Mediator function is that it serves as a direct intermediary between DNA-bound activators and the general transcription machinery. However, yeast genetic studies have revealed two important functional properties of the complex that are not compatible with this simple model. The first is Mediator's ability to repress transcription of a large number of genes via a possible link to chromatin structure. The second is the additional co-activator complexes and specific core promoter sequences required for Mediator function in activated transcription. Although ably studied by yeast genetic techniques over the past 10 to 15 years, very little is known about the direct mechanisms used by Mediator to facilitate these functions. Our proposed research meets a critical need by using biochemical experiments to reveal the mechanistic basis of these novel functional properties of Mediator. The long-term goal of our research program is to obtain a complete molecular understanding of the 'communication' between activation or repression signals and the core transcription machinery in eukaryotic cells. Our proposed studies of yeast Mediator center on the use of purified proteins and nucleic acids to elucidate mechanisms. They also marshal the substantial genetic, genomic and proteomic resources in yeast to understand these mechanisms in a physiological context. Our central hypothesis is that Mediator facilitates repression and co-operates with other co-activators through mechanisms that are distinct from serving as a direct intermediary between activators and RNA Polymerase II. The specific aims of the current research project will answer two key questions. First, how are Mediator-facilitated and chromatin-based transcription repression linked? We propose biochemical and genetic experiments to elucidate a mechanism of repression that involves direct interactions between Mediator and chromatin. Second, how do SAGA, TFIID, and core promoter sequence affect Mediator activated transcription? We have designed biochemical experiments to determine how and if Mediator directly works with different co-activators to stimulate high levels of activated transcription in a cooperative manner. These studies are essential to understand the full range of transcriptional mechanisms used to regulate cellular and developmental processes.

介体是一种全局性的转录共调节蛋白复合物，在转录调控中起着核心作用。 RNA聚合酶II转录基因的激活和抑制。高度保守的调解人的组成和功能，以及其机制的复杂性，使酿酒酵母是深入分子研究的理想模型。当前范式介体功能的一个重要方面是它作为DNA结合激活剂之间的直接中介和一般的转录机制。然而，酵母基因研究揭示了两个与这个简单模型不相容的复杂的重要功能特性。第一个是Mediator能够通过一个可能的抑制因子抑制大量基因的转录。连接到染色质结构。第二种是额外的共活化剂复合物和特异性激活转录中介体功能所需的核心启动子序列。虽然在过去的10到15年里，酵母遗传技术进行了巧妙的研究，但对调解员为促进这些职能而使用的直接机制。我们提出的研究通过使用生物化学实验来揭示这些的机械基础， Mediator的新功能特性。我们研究计划的长期目标是获得一个完整的分子理解激活或抑制信号与核心之间的“通信” 真核细胞中的转录机制。我们对酵母介体的研究主要集中在使用纯化的蛋白质和核酸来阐明机制。他们还将酵母中大量的遗传、基因组和蛋白质组资源，以了解这些生理学上的机制。我们的中心假设是，调解人促进抑制和合作与其他共激活剂通过机制，是不同的作为激活剂和RNA聚合酶II之间的直接中介。具体目标目前的研究项目将回答两个关键问题。第一，调解员如何协助和基于染色质的转录抑制有关吗我们建议生物化学和遗传学实验来阐明抑制机制，涉及直接相互作用之间介体和染色质。其次，佐贺、TFIID和核心启动子序列如何影响中介激活转录？我们设计了生化实验来确定如果Mediator直接与不同的辅激活剂一起工作，以合作的方式进行转录。这些研究对于了解用于调节细胞和发育过程的转录机制。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Histone modifications influence mediator interactions with chromatin.

DOI：
10.1093/nar/gkr551
发表时间：
2011-10
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Zhu X;Zhang Y;Bjornsdottir G;Liu Z;Quan A;Costanzo M;Dávila López M;Westholm JO;Ronne H;Boone C;Gustafsson CM;Myers LC
通讯作者：
Myers LC

Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp.