Activator-Targeted Subunits of the ARC/Mediator

ARC/Mediator 的激活子靶向亚基

• 批准号: 7191752
• 负责人: ANDERS M NAAR
• 金额: $ 33.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191752
• 关键词: Activator Appliances; Address; Alzheimer' s Disease; Atherosclerosis; Binding; Binding Proteins; Chemical Modifier; Cholesterol; Chromatin; Class; Clinical; Cloning; Complex; DNA Microarray Chip; DNA Microarray format; Data; Disease; Docking; Dominant-Negative Mutation; EP300 gene; Family; Family member; Fatty Acids; Gene Activation; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Homeostasis; Human; In Vitro; Individual; Investigation; Knowledge; Malignant Neoplasms; Mediating; Mediator of activation protein; Microarray Analysis; Molecular; Numbers; Principal Investigator; RNA Interference; RNA Polymerase II; Recruitment Activity; Regulator Genes; Regulatory Element; Relative (related person); Role; SREBP-1a; Signal Transduction; Sterols; Structure; System; Transcription Coactivator; Transcriptional Regulation; Work; Yeasts; base; cholesterol control; chromatin immunoprecipitation; cofactor; fatty acid biosynthesis; in vivo; insight; novel; programs; research study; transcription factor

DESCRIPTION (provided by applicant): Abnormalities in cholesterol and fatty acid homeostasis have been implicated in a number of common diseases, such as atherosclerosis, Alzheimer's disease, and cancers. SREBPs are critical regulators of genes controlling cholesterol and fatty acid homeostasis, hence elucidation of the molecular mechanism of transcription regulation by SREBPs could assist efforts to identify novel chemical modifiers of cholesterol and fatty acid biosynthesis that may have clinical utility. We will dissect the role of the ARC/Mediator coactivator in SREBP gene regulation. The Specific Aims are: I. To determine the functional role of ARC/Mediator and the ARC105 subunit in gene activation by the SREBP family of transcription factors. We will determine the functional involvement of the ARC/Mediator and ARC 105 in transcription control by the SREBP family of activators using our chromatin based in vitro transcription system and RNAi followed by DNA microarray analysis. These studies will clarify the role of the ARC/Mediator in SREBP gene activation programs, and increase our understanding of the ARC105 subunit as a critical activator-target. II. To determine whether KIX domains in distinct co-activators serve as functionally important interaction modules for SREBPs. We will examine how SREBPs interact molecularly and functionally with the putative ARC105 KIX domain in comparison with the CBP and p300 KIX domains. These studies will determine whether KIX domains in different types of co-activators may serve as docking modules for SREBPs and will provide insights into how certain activators can bind multiple co-activators. III. To identify the molecular and functional interplay of activators and co-activators at SREBP target genes. We will use a combination of RNAi and chromatin immunoprecipitation (ChIP) to determine the dynamic interplay of SREBPs and the ARC/Mediator and CBP/p300 co-activators on different SREBP target genes in vivo. The proposed investigations will further our understanding of the individual, cooperative, or competitive roles of activators and KIX domain-containing co-activators and their recruitment dynamics in SREBP-dependent gene activation in vivo.

描述（由申请人提供）： 胆固醇和脂肪酸稳态异常与许多常见疾病有关，例如动脉粥样硬化、阿尔茨海默病和癌症。 SREBP 是控制胆固醇和脂肪酸稳态的基因的关键调节因子，因此阐明 SREBP 转录调节的分子机制可以帮助鉴定可能具有临床实用性的胆固醇和脂肪酸生物合成的新型化学修饰剂。我们将剖析 ARC/Mediator 共激活因子在 SREBP 基因调控中的作用。具体目标是： I. 确定 ARC/Mediator 和 ARC105 亚基在 SREBP 转录因子家族基因激活中的功能作用。我们将使用我们基于染色质的体外转录系统和 RNAi，然后进行 DNA 微阵列分析，确定 ARC/Mediator 和 ARC 105 在 SREBP 激活剂家族转录控制中的功能参与。这些研究将阐明 ARC/Mediator 在 SREBP 基因激活程序中的作用，并加深我们对 ARC105 亚基作为关键激活剂靶标的理解。二.确定不同共激活剂中的 KIX 结构域是否充当 SREBP 功能上重要的相互作用模块。我们将研究 SREBP 如何与假定的 ARC105 KIX 结构域在分子和功能上相互作用，并与 CBP 和 p300 KIX 结构域进行比较。这些研究将确定不同类型共激活剂中的 KIX 结构域是否可以充当 SREBP 的对接模块，并将深入了解某些激活剂如何结合多个共激活剂。三．鉴定 SREBP 靶基因激活剂和共激活剂的分子和功能相互作用。我们将结合使用 RNAi 和染色质免疫沉淀 (ChIP) 来确定 SREBP 与 ARC/Mediator 和 CBP/p300 共激活剂在体内不同 SREBP 靶基因上的动态相互作用。拟议的研究将进一步了解激活剂和包含 KIX 结构域的共激活剂的个体、合作或竞争作用，以及它们在体内 SREBP 依赖性基因激活中的招募动态。