Nuclear hormone receptors in adipocyte differentiation

脂肪细胞分化中的核激素受体

• 批准号: 7516609
• 负责人: MITCHELL A. LAZAR
• 金额: $ 45.15万
• 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/7516609
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Adverse effects; Antidiabetic Drugs; Binding; Binding Sites; Biological; Candidate Disease Gene; Cardiovascular Diseases; Chromosome Mapping; Class; Complex; Data; Depth; Diabetes Mellitus; Epidemic; Epigenetic Process; Evaluation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genome; 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; Numbers; 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; concept; density; design; enzyme activity; gene function; gene induction/repression; genome-wide analysis; improved; innovation; insight; insulin sensitivity; lipid biosynthesis; macrophage; novel; promoter; response; transcription factor

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，从而提高胰岛素敏感性但会引起不受欢迎的副作用。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结合的不同模式决定了PPAR3与合作转录因子之间的协同作用，从而导致了靶基因上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。具体目的1是在全基因组范围内描绘脂肪细胞中的PPAR3基因靶标，并了解其调节模式。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与功能之间的复杂关系。利用染色质免疫沉淀（CHIP）的初步数据，然后与高密度基因组阵列杂交揭示了与大量新型基因靶标的PPAR3结合，与转录起始位点不同，与其他转录因子合作。具体目的2是确定脂肪形成过程中发生的表观遗传变化及其与PPAR3结合的关系。 PPAR3募集了具有酶活性的核心测量剂，但对内源性靶基因的组蛋白修饰知之甚少。我们假设在脂肪生成和使用配体的脂肪细胞处理后，靶基因调节是由与PPAR3结合模式相关的表观遗传标记模式确定的，例如直接或间接，并与特定的转录因子合作。初步数据表明，脂肪形成和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。第三个具体目的是了解PPAR3调节细胞型特异性基因的机制。 PPAR3在脂肪细胞中以最高水平表达，但在巨噬细胞中也表达并在其功能重叠但具有显着差异的巨噬细胞中发挥作用。我们假设该组织特异性是由于差异PPAR3基因定位，合作转录因子和表观遗传调节所致。这将通过全基因组的PPAR3位置分析以及巨噬细胞中的信息表观遗传标记来测试。与脂肪细胞中PPAR3功能的比较将揭示组织选择性的机制，这些机制可以在设计为选择性调节基因表达的PPAR3调节剂中被利用。总体而言，这些创新研究将产生对PPAR3及其在掺杂和代谢中的作用的主要新见解。从这项工作中获得的知识将为关键生物学途径的转录和表观遗传控制（包括代谢和炎症）提供新的启示，并有可能导致对包括肥胖症和糖尿病在内的新陈代谢疾病的新和更深入的见解，以及现代社会中流行病的人类疾病。相关性了解脂肪细胞中基因的调节方式将提供对肥胖症的见解，肥胖症的特征是脂肪细胞增加和异常。对核受体PPAR3的关注是合适的，因为这是脂肪细胞形成和功能的主要调节剂，也是抗糖尿病药物的靶标，可减轻胰岛素抵抗，这是肥胖症的毁灭性后果。因此，从这项工作中获得的见解可能会导致新的和更深入的见解，这些见解可能转化为新的代谢疾病治疗策略，包括肥胖，糖尿病和心血管疾病。