HNF-4 and coactivators in apoAl gene regulation

HNF-4 和 apoAl 基因调控中的共激活因子

• 批准号: 7322128
• 负责人: SOHAIL MALIK
• 金额: $ 33.21万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322128
• 关键词: Apolipoprotein A-I; Area; Atherosclerosis; Binding; Biological Assay; Cardiovascular system; Cell-Free System; Cells; Chromatin; Complement; Complex; Condition; DNA-Directed RNA Polymerase; DNA-Protein Interaction; Dependency; Developed Countries; Developing Countries; Development; Elements; Embryonic Development; Endoderm; Enhancers; Fetal Liver; Future; Gene Expression; Gene Expression Regulation; General Transcription Factors; Genes; Genetic Transcription; Goals; Hepatitis B; Hepatocyte; High Density Lipoproteins; Histones; Homeostasis; Hormonal; Hypertension; In Vitro; Life; Liver; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nucleic Acid Regulatory Sequences; Pathway interactions; Plasma; Proteins; RNA Polymerase II; Range; Series; Signal Transduction; Stimulus; Structural Protein; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Transferase; Visceral; Work; Yolk Sac; base; chromatin immunoprecipitation; cofactor; design; in vivo; mature animal; mortality; promoter; transcription factor

DESCRIPTION (provided by applicant): This proposal aims to obtain a detailed molecular understanding of how the gene for apolipoprotein AI (apoAI) is transcriptionally regulated in liver cells. ApoAI is the major protein component of high-density lipoprotein, HDL, whose plasma levels are inversely correlated with atherosclerosis, a leading cause of mortality and morbidity in developed countries. An aim of the project is also to understand the mechanism by which the orphan nuclear receptor HNF-4, previously implicated in apoAI transcriptional control, activates transcription by RNA polymerase II. In addition to apoAI, HNF-4 regulates many genes involved in the "metabolic syndrome" [including hypertension and non-insulin dependent diabetes mellitus (NIDDM)]. Also, its gene was independently isolated as the causative factor for maturity onset diabetes of the young (MODY1). Furthermore, HNF-4 is a major transcription factor for hepatitis B viral gene expression, an etiologic agent for liver cancer. The project is therefore expected to have broad relevance. Cellular and in vitro methods will be employed to identify transcription factors that are required for HNF-4-mediated activation at the liver-specific enhancer of the apoAI gene. Transcription factors under study will include another liver-enriched factor, HNF-3 (known to synergistically function with HNF-4), Mediator (the global coactivator recently shown to be necessary for HNF-4 function) and key chromatin cofactors (histone acetyl transferases, ATP-remodeling). Cellular analyses (chromatin immunoprecipitation [ChIP]) will delineate transcription factor interactions in living cells. Both steady-state expression of the apoAI gene in mature hepatocytes, as well as the pathway leading to the initial onset of apoAI gene expression in developing mouse embryoid bodies (in culture) will be monitored. In vitro approaches will complement these in vivo studies. Thus, functional (in vitro transcription from chromatin templates to recapitulate core features of apoAI gene regulation) and structural (protein-protein and protein-DNA interactions) analyses will also be undertaken. Together, the proposed studies will permit understanding of the mechanistic basis for the synergistic function of the relevant transcription factors, which regulate apoAI gene expression in vivo and contribute to its homeostasis. They will also potentially reveal targets for future therapeutic developments in the metabolic and cardiovascular areas.

描述（由申请人提供）：该提案旨在获得对载脂蛋白AI（APOAI）基因如何在肝细胞中转录调节的详细分子理解。 ApoAI是高密度脂蛋白HDL的主要蛋白质成分，其血浆水平与动脉粥样硬化成反比，这是发达国家死亡率和发病率的主要原因。该项目的目的也是了解以前与ApoAI转录控制有关的孤儿核受体HNF-4的机制，它通过RNA聚合酶II激活转录。除APOAI外，HNF-4还调节了许多参与“代谢综合征”的基因[包括高血压和非胰岛素依赖性糖尿病（NIDDM）]。同样，其基因被独立地分离为年轻糖尿病（Mody1）成熟糖尿病的病因。此外，HNF-4是乙型肝炎病毒基因表达的主要转录因子，这是肝癌的病因学剂。因此，该项目有望具有广泛的相关性。将采用细胞和体外方法来识别APOAI基因的肝特异性增强子处HNF-4介导的激活所需的转录因子。研究的转录因子将包括另一个富含肝脏的因子HNF-3（已知与HNF-4协同功能），介体（最近证明的全局共激活因子是HNF-4功能所必需的）和关键的染色质辅助因子（组蛋白乙酰基乙酰基辅助剂（组蛋白乙酰基转移酶，ATP-射量）。细胞分析（染色质免疫沉淀[CHIP]）将描绘活细胞中的转录因子相互作用。在成熟的肝细胞中，ApoAI基因的稳态表达以及导致在发育中的小鼠胚胎体（在培养中）初始发作的途径。体外方法将补充这些体内研究。因此，还将进行功能性（从染色质模板中转录以概括ApoAI基因调节的核心特征）和结构性（蛋白质 - 蛋白质和蛋白-DNA相互作用）分析。拟议的研究一起，将允许了解相关转录因子的协同功能的机械基础，这些转录因子调节体内apoAI基因的表达并有助于其稳态。他们还将有可能揭示代谢和心血管区域未来治疗发展的目标。

项目成果

PIC Activation through Functional Interplay between Mediator and TFIIH.

通过介体和 TFIIH 之间的功能相互作用激活 PIC。

• DOI: 10.1016/j.jmb.2016.11.026
• 发表时间: 2017
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Malik,Sohail;Molina,Henrik;Xue,Zhu
• 通讯作者: Xue,Zhu

Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.

• DOI: 10.1084/jem.20081188
• 发表时间: 2008-09-29
• 期刊: The Journal of experimental medicine
• 作者: El-Osta A;Brasacchio D;Yao D;Pocai A;Jones PL;Roeder RG;Cooper ME;Brownlee M
• 通讯作者: Brownlee M

Mediator-regulated transcription through the +1 nucleosome.

• DOI: 10.1016/j.molcel.2012.10.009
• 发表时间: 2012-12-28
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Nock, Adam;Ascano, Janice M.;Barrero, Maria J.;Malik, Sohail
• 通讯作者: Malik, Sohail

Identification of DNA-dependent Protein Kinase as a Cofactor for the Forkhead Transcription Factor FoxA2

鉴定 DNA 依赖性蛋白激酶作为叉头转录因子 FoxA2 的辅助因子

• DOI: 10.1074/jbc.m109.016295
• 发表时间: 2009
• 期刊: J Biol Chem
• 影响因子: 4.8
• 作者: Nock;J. M. Ascano;T. Jones;M. J. Barrero;N. Sugiyama;M. Tomita;Y. Ishihama;and S. Malik
• 通讯作者: and S. Malik