Nuclear hormone receptors in adipocyte differentiation

脂肪细胞分化中的核激素受体

• 批准号: 7826663
• 负责人: MITCHELL A. LAZAR
• 金额: $ 46.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826663
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Adverse effects; Antidiabetic Drugs; Binding; Binding Sites; Biological; Candidate Disease Gene; Cardiovascular Diseases; Chromosome Mapping; Complex; Data; Diabetes Mellitus; Epidemic; Epigenetic Process; Evaluation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genomics; Goals; Grant; Histone Acetylation; Histones; Inflammation; Insulin Resistance; Knowledge; Laboratories; Lead; Ligands; Light; Location; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methylation; Modification; Molecular; Nuclear Hormone Receptors; Nuclear Receptors; Obesity; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Process; Recruitment Activity; Regulation; Resolution; Role; Site; Societies; Specificity; Sum; Testing; Thiazolidinediones; Tissues; Translating; Work; adipocyte differentiation; cell type; chromatin immunoprecipitation; density; design; enzyme activity; gene function; gene induction/repression; genome wide association study; genome-wide; genome-wide analysis; histone modification; improved; innovation; insight; insulin sensitivity; lipid biosynthesis; macrophage; novel; promoter; response; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear hormone receptor peroxisome proliferator-activated receptor 3 (PPAR3) controls adipogenesis and mediates antidiabetic effects of drugs that improve insulin sensitivity but cause unwanted side effects. We hypothesize that target gene- and tissue-selective modulation of gene expression by PPAR3 are dictated by different modes of PPAR3 binding and synergy between PPAR3 and cooperating transcription factors, leading to a defining spectrum of epigenetic marks on target genes. To test this concept, we are performing genome-wide analysis of PPAR3 binding and epigenetic changes during adipogenesis. Specific Aim 1 is to delineate PPAR3 gene targets in adipocytes on a genome-wide scale, and understand their modes of regulation. We hypothesize that target gene-specific regulation of adipocyte gene expression by PPAR3 is due to complex relationships between binding and function. Preliminary data utilizing chromatin immunoprecipitation (ChIP) followed by hybridization to high density genomic arrays reveals PPAR3 binding to a large number of novel gene targets, at varying distances from transcriptional start sites, in cooperation with other transcription factors. Specific Aim 2 is to determine the epigenetic changes that occur during adipogenesis and their relation to PPAR3 binding. PPAR3 recruits coregulators with enzyme activity, but little is known about the histone modifications at endogenous target genes. We hypothesize that, during adipogenesis and upon treatment of adipocytes with ligands, target gene regulation is determined by patterns of epigenetic marks related to the mode of PPAR3 binding, e.g. direct or indirect, and to cooperation with specific transcription factors. Preliminary data show that adipogenesis and PPAR3 ligands indeed influence histone acetylation and methylation on a genome-wide scale, in a target-gene and function-specific manner. The Third Specific Aim is to understand the mechanisms of cell-type specific gene regulation by PPAR3. PPAR3 is expressed at highest levels in adipocytes, but is also expressed and functional in macrophages, where its functions overlap but have significant differences. We hypothesize that this tissue-specificity is due to differential PPAR3 gene localization, cooperating transcription factors, and epigenetic regulation. This will be tested by genome-wide location analysis of PPAR3 as well as informative epigenetic marks in macrophages. Comparison with PPAR3 function in adipocytes will reveal mechanisms of tissue-selectivity that can be exploited in designing PPAR3 modulators that selectively regulate gene expression. Overall, these innovative studies will generate major new insights into PPAR3 and its role in adipogenesis and metabolism. The knowledge gained from this work will shed new light on the transcriptional and epigenetic control of key biological pathways, including metabolism and inflammation, with the potential to lead to new and deeper insights into metabolic disorders, including obesity and diabetes, and cardiovascular disease, that are epidemic in modern society. Relevance Understanding how genes are regulated in fat cells will provide insight into obesity, which is characterized by increased and abnormal fat cells. The focus on the nuclear receptor PPAR3 is appropriate because this is the master regulator of fat cell formation and function, and a target of anti-diabetic drugs that mitigate insulin resistance that is a devastating consequence of obesity. Thus, the insights gained from this work are likely to lead to new and deeper insights that may be translated into novel treatment strategies for metabolic disorders, including obesity, diabetes, and cardiovascular disease.

描述（由申请人提供）：该实验室的一个主要目标是了解核激素受体过氧化物酶体增殖物激活受体 3 (PPAR3) 控制脂肪生成并介导药物的抗糖尿病作用的分子机制，这些药物可提高胰岛素敏感性，但会导致不良副作用影响。我们假设 PPAR3 对基因表达的靶基因和组织选择性调节是由 PPAR3 结合的不同模式以及 PPAR3 和协同转录因子之间的协同作用决定的，从而导致靶基因上的表观遗传标记的定义谱。为了测试这个概念，我们正在对脂肪生成过程中 PPAR3 结合和表观遗传变化进行全基因组分析。具体目标 1 是在全基因组范围内描绘脂肪细胞中的 PPAR3 基因靶点，并了解其调控模式。我们假设 PPAR3 对脂肪细胞基因表达的靶基因特异性调节是由于结合和功能之间的复杂关系。利用染色质免疫沉淀 (ChIP) 和高密度基因组阵列杂交的初步数据显示，PPAR3 与其他转录因子合作，与转录起始位点不同距离处的大量新基因靶标结合。具体目标 2 是确定脂肪生成过程中发生的表观遗传变化及其与 PPAR3 结合的关系。 PPAR3 招募具有酶活性的共调节因子，但人们对内源靶基因的组蛋白修饰知之甚少。我们假设，在脂肪形成过程中以及用配体处理脂肪细胞时，靶基因调控是由与 PPAR3 结合模式相关的表观遗传标记模式决定的，例如 PPAR3 结合模式。直接或间接，以及与特定转录因子的合作。初步数据表明，脂肪生成和 PPAR3 配体确实以靶基因和功能特异性方式在全基因组范围内影响组蛋白乙酰化和甲基化。第三个具体目标是了解 PPAR3 细胞类型特异性基因调控的机制。 PPAR3在脂肪细胞中表达水平最高，但也在巨噬细胞中表达并发挥作用，其功能重叠但有显着差异。我们假设这种组织特异性是由于 PPAR3 基因定位差异、转录因子协同作用和表观遗传调控所致。这将通过 PPAR3 的全基因组定位分析以及巨噬细胞中的信息表观遗传标记进行测试。与脂肪细胞中 PPAR3 功能的比较将揭示组织选择性机制，可用于设计选择性调节基因表达的 PPAR3 调节剂。总体而言，这些创新研究将为 PPAR3 及其在脂肪生成和代谢中的作用产生重要的新见解。从这项工作中获得的知识将为关键生物途径（包括代谢和炎症）的转录和表观遗传控制提供新的线索，并有可能对代谢紊乱（包括肥胖和糖尿病以及心血管疾病）产生新的、更深入的见解，是现代社会的流行病。相关性 了解基因在脂肪细胞中的调节方式将有助于深入了解肥胖症，其特点是脂肪细胞增多和异常。对核受体 PPAR3 的关注是适当的，因为它是脂肪细胞形成和功能的主要调节因子，也是减轻胰岛素抵抗（肥胖的破坏性后果）的抗糖尿病药物的靶点。因此，从这项工作中获得的见解可能会带来新的、更深入的见解，这些见解可能转化为代谢性疾病（包括肥胖、糖尿病和心血管疾病）的新治疗策略。