Mechanisms of TLE3 Action in Adipose Subtype-selective Gene Expression

TLE3 在脂肪亚型选择性基因表达中的作用机制

基本信息

批准号：
8834969
负责人：
Prashant Rajbhandari
金额：
$ 5.15万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2017-09-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834969
关键词：
2,4-thiazolidinedione Ablation Address Adenovirus Vector Adipocytes Adipose tissue Adrenergic Agonists Affect Binding Biological Brown Fat Cardiovascular Diseases Cells ChIP-on-chip ChIP-seq Chemicals Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Data Diet Energy Metabolism Enhancers Epigenetic Process Equilibrium Exhibits Exposure to Fatty acid glycerol esters Financial compensation Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genome Goals Harvest Heart Diseases Heating Homeostasis Hydrolysis Individual Insulin Resistance Knock-out Ligands Lipids Mammals Mediating Metabolic Metabolic Diseases Methodology Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Receptors Nucleic Acid Regulatory Sequences Obesity PPAR gamma Pathogenesis Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phenotype Physiological Play Procedures Publishing RNA Recruitment Activity Regulation Research Project Grants Role Site Testing Therapeutic Thermogenesis Thiazolidinediones Time Tissue Differentiation Tissue-Specific Gene Expression Transgenic Organisms Translating Triglycerides adipocyte differentiation base chromatin modification combat genome-wide histone modification insight lipid biosynthesis loss of function overexpression oxidation programs promoter public health relevance research study rosiglitazone transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Adipose tissue plays an important role in energy homeostasis by storing dietary energy in the form of triglyceride and releasing free fatty acids through hydrolysis of triglycerides in times of metabolic need. The study of adipocyte differentiation is becoming increasingly important given the role of adipose tissue in the pathogenesis of metabolic diseases such as obesity, insulin resistance, and cardiovascular diseases. Mammals have distinct specialized types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores energy whereas BAT is specialized to dissipate stored chemical energy in the form of heat and may have anti-obesity function. Recent studies have revealed an inherent plasticity of WAT to exhibit genetic and physiological features of BAT upon exposure to cold, ?-adrenergic agonists, or thiazolidinediones. The center of this phenotypic switch is peroxisome proliferator- activated receptor gamma (PPAR?), a master transcriptional regulator of both WAT and BAT differentiation. PPAR? is required for terminal adipocyte differentiation, as mice deficient for this nuclear receptor lack both WAT and BAT. The mechanism by which PPAR? directs adipose subtype-specific gene expression programs is still unclear. We recently discovered TLE3 as a dual-function WAT-specific PPAR? coregulator that forms both active and repressive transcriptional complexes to respectively drive WAT and suppress BAT differentiation. Moreover, our unpublished preliminary ChIP-Seq and RNA-Seq data show that i) genome-wide TLE3 binding correlates with both PPAR? enrichment on adipogenic regulatory sites and the regulation of adipose subtype-specific gene expression and ii) TLE3 binding is enriched in DNA regions containing several different pro-adipogenic transcription factor motifs. In this proposal we aim to determine the role of PPAR?:TLE3 axis in the nucleation of transcription factors and epigenetic modifications for WAT- and BAT-specific gene expression. We will also examine the consequence of TLE3 ablation on global adipocyte gene expression and PPAR? occupancy on gene promoter/enhancers. Overall, the concepts and methodologies used in this proposal will highlight the intricate balance between transcriptional programs and adipose-specific phenotype that may facilitate therapeutic manipulation of energy expenditure in patients with obesity and metabolic disorders.

描述（由申请人提供）：脂肪组织以甘油三酯的形式储存膳食能量，并在代谢需要时通过甘油三酯的水解释放游离脂肪酸，从而在能量稳态中发挥重要作用。鉴于脂肪组织在肥胖、胰岛素抵抗和心血管疾病等代谢疾病发病机制中的作用，脂肪细胞分化的研究变得越来越重要。哺乳动物具有不同类型的脂肪组织：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。 WAT 储存能量，而 BAT 专门以热量的形式消耗储存的化学能，并且可能具有抗肥胖功能。最近的研究表明，WAT 具有固有的可塑性，在接触冷、β-肾上腺素能激动剂或噻唑烷二酮类药物时，会表现出 BAT 的遗传和生理特征。这种表型转换的中心是过氧化物酶体增殖物激活受体 γ (PPAR?)，它是 WAT 和 BAT 分化的主要转录调节因子。过氧化物酶体活化受体？是终末脂肪细胞分化所必需的，因为缺乏这种核受体的小鼠同时缺乏 WAT 和 BAT。 PPAR的作用机制是什么？指导脂肪亚型特异性基因表达程序仍不清楚。我们最近发现 TLE3 作为一种双功能 WAT 特异性 PPAR？核心调节子，形成活性转录复合物和抑制性转录复合物，分别驱动 WAT 和抑制 BAT 分化。此外，我们未发表的初步 ChIP-Seq 和 RNA-Seq 数据表明 i) 全基因组 TLE3 结合与 PPAR?脂肪形成调节位点的富集和脂肪亚型特异性基因表达的调节，以及 ii) TLE3 结合在含有几种不同的促脂肪形成转录因子基序的 DNA 区域中富集。在本提案中，我们的目的是确定 PPAR?:TLE3 轴在转录因子成核和 WAT 和 BAT 特异性基因表达的表观遗传修饰中的作用。我们还将研究 TLE3 消融对整体脂肪细胞基因表达和 PPAR 的影响？基因启动子/增强子的占据。总体而言，该提案中使用的概念和方法将强调转录程序和脂肪特异性表型之间的复杂平衡，这可能有助于肥胖和代谢紊乱患者能量消耗的治疗控制。