Gene Networks promoting adipocyte cell differentiation and function

促进脂肪细胞分化和功能的基因网络

• 批准号: 10609053
• 负责人: Patrick Seale
• 金额: $ 45.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609053
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Binding Sites; Biological; Biological Assay; Biological Process; Biology; Body Weight; Brown Fat; CCAAT-Enhancer-Binding Protein-beta; Cell Density; Cell Differentiation process; Cell physiology; Cells; Chemicals; Chromatin; Collaborations; Complex; DNA; Data; Data Set; Detection; Development; Diabetes Mellitus; Disease; Enhancers; Exposure to; Fatty acid glycerol esters; Gene Expression; Generations; Genes; Genetic Screening; Genetic Transcription; Genomics; Glucocorticoid Receptor; Goals; Growth and Development function; Health; Health Benefit; Heart Diseases; Homeostasis; Human; Hyperlipidemia; Hypertension; Kinetics; Laboratories; Mass Spectrum Analysis; Mesenchymal Stem Cells; Metabolic Diseases; Metabolism; Modification; Molecular; Multipotent Stem Cells; Mus; Mutation Analysis; Normal tissue morphology; Obesity; Obesity Epidemic; Organ; PPAR gamma; Physiological; Play; Population; Proteins; Proteome; Proteomics; Risk; Role; Signal Transduction; Tissue-Specific Gene Expression; Tissues; United States; Visceral; activating transcription factor 4; adipocyte differentiation; candidate identification; cell type; combat; diet and exercise; epigenomics; fighting; gene network; gene repression; genome-wide analysis; in vivo; insight; knockout animal; knockout gene; lipid biosynthesis; lipid metabolism; novel; paralogous gene; programs; recruit; response; stem cell fate; subcutaneous; therapeutic target; transcription factor; translational potential

A major goal of this laboratory is to understand the molecular mechanisms by which TFs and epigenomic modification control gene expression programs that regulate adipose tissue development and function. Adipogenesis begins with an established cascade of transcription factor (TF) activity that includes collaboration between the CCAAT/enhancer binding protein β (CEBPβ) and the glucocorticoid receptor (GR). A key goal of the present proposal is to determine how CEBPβ and its related paralogs bridge the transcriptional programs in multipotent stem cells and early differentiating pre-adipocytes, with a long-term objective of understanding a comprehensive TF network promoting adipose tissue development, growth and function. Specific Aim 1 comprehensively identifies the components of active enhancers during human adipogenesis. We will perform a state-of-the-art genomic/proteomic approach to determine the chromatin-associated proteins promoting adipocyte differentiation. Specific Aim 2 elucidates the mechanistic actions of networked TFs and co-regulators that control human adipogenesis and adipocyte function. Novel adipogenic roles for protein candidates identified in Aims 1 will be examined by mutational analysis and genome-wide approaches. As a whole, we will generate and integrate unique, orthogonal cistromic and enhancer proteomic datasets to reveal fundamental molecular mechanisms for transcriptional regulators in native chromatin. This will elucidate how CEBP proteins and GR perform unique biological functions, and address the more general question of how TFs recognize, access and act at their genomic-binding sites to control tissue-specific gene expression. Specific Aim 3 comprehensively identifies the components of active enhancers in adipose tissue. We hypothesize that comparison of the enhancer proteomes from visceral and subcutaneous white adipose tissues and from brown adipose tissue will reveal fundamental mechanisms controlling depot-specific gene expression and uncover the set of transcriptional regulators controlling lipid metabolism in vivo. Our focus on the development and function of adipose tissue is warranted given its importance in health and disease. Indeed, adipose tissue normally benefits health, yet in excess as in obesity, it becomes a strong risk for metabolic diseases including diabetes, hyperlipidemia, hypertension and heart disease. New insights into adipose biology will enhance its translational potential to combat the harmful and growing epidemics of obesity and diabetes.

该实验室的主要目标是了解TFS和表观基因组的分子机制 修饰控制基因表达程序，调节脂肪组织的发育和功能。 脂肪形成始于既定的转录因子级联（TF）活动，其中包括协作 在CCAAT/增强子结合蛋白β（CEBPβ）和糖皮质激素受体（GR）之间。一个关键目标 目前的建议是确定CEBPβ及其相关的旁系同源者如何桥接转录程序 多能干细胞和早期区分前脂肪细胞，其长期目标是理解 综合的TF网络促进脂肪组织的发展，生长和功能。具体目标1 全面识别人脂肪形成过程中主动增强子的成分。我们将 执行最先进的基因组/蛋白质组学方法来确定与染色质相关的蛋白 促进脂肪细胞分化。特定目标2阐明了网络TF的机械作用 以及控制人类脂肪形成和脂肪细胞功能的共同调节剂。新颖的成脂作用 AIM 1中鉴定出的蛋白质候选物将通过突变分析和全基因组方法进行检查。 总体而言，我们将生成和集成独特的，正交的Cistromic和Enhancer蛋白质组学数据集 揭示了天然染色质转录调节剂的基本分子机制。这将阐明 CEBP蛋白质和GR如何执行独特的生物学功能，并解决更普遍的问题 TF如何在其基因组结合位点识别，访问和作用以控制组织特异性基因表达。 特定目标3全面识别脂肪组织中活性增强子的成分。我们 假设比较来自内脏和皮下白脂肪的增强子蛋白质组 组织和棕色脂肪组织将揭示控制仓库特异性基因的基本机制 表达并揭示了控制体内脂质代谢的转录调节剂的集合。我们专注于 鉴于其在健康和疾病中的重要性，脂肪组织的发展和功能是有必要的。 实际上，脂肪组织通常会使健康受益，但与肥胖一样过多，它成为强烈的风险 包括糖尿病，高脂血症，高血压和心脏病在内的代谢疾病。新的见解 脂肪生物学将增强其转化潜力，以应对肥胖的有害和增长的发作 和糖尿病。