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

• 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
• 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

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）：脂肪组织通过在代谢需求时以甘油三酸酯的形式储存饮食能量，并通过甘油三酸酯的水解来释放游离脂肪酸，在能量稳态中起重要作用。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的发病机理中的作用，脂肪细胞分化的研究变得越来越重要。哺乳动物具有独特的专门类型的脂肪组织：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。 WAT存储能量，而BAT专门以热的形式耗散储存的化学能，并且可能具有抗肥胖功能。最近的研究表明，在暴露于冷，肾上腺素能激动剂或噻唑烷二酮时，WAT具有固有的WAT可塑性。该表型开关的中心是过氧化物酶体增殖物激活的受体伽马（PPAR？），这是WAT和BAT分化的主转录调节剂。 ppar？对于末端脂肪细胞分化所必需的，因为缺乏该核受体的小鼠缺乏WAT和BAT。哪种PPAR的机制？直接脂肪亚型特异性基因表达程序尚不清楚。我们最近发现TLE3是双功能特异性PPAR吗？形成活跃和抑制转录复合物以分别驱动WAT并抑制蝙蝠分化的核心测量器。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结合与两个PPAR相关？对成脂调节位点的富集以及脂肪亚型特异性基因表达和II）TLE3结合富集在包含几种不同促脂化转录因子基序的DNA区域。在此提案中，我们旨在确定PPAR？：TLE3轴在转录因子的成核和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消融对全局脂肪细胞基因表达和PPAR的后果吗？基因启动子/增强子的占用率。总体而言，该提案中使用的概念和方法将突出转录程序和脂肪特异性表型之间的复杂平衡，这些平衡可能有助于肥胖和代谢性疾病患者的能量消耗。