Transcriptional and epigenetic regulation of thermogenic adipocyte program

产热脂肪细胞程序的转录和表观遗传调控

• 批准号: 10604352
• 负责人: Yu-Hua Tseng
• 金额: $ 62.34万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604352
• 关键词: 3-Dimensional; ATAC-seq; ATP Synthesis Pathway; Ablation; Achievement; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affect; Architecture; Area; Binding; Bioenergetics; Bioinformatics; Biology; Brown Fat; CRISPR screen; CRISPR/Cas technology; Cardiometabolic Disease; Cardiovascular Diseases; Cell Aging; Cell Nucleus; Cell Respiration; Cells; ChIP-seq; Chromatin; Chromatin Loop; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deposition; Distal; Elements; Energy Metabolism; Enhancers; Epigenetic Process; Event; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Genome Mappings; Genomics; Histones; Human; Impairment; Knockout Mice; Knowledge; LIM Domain; Low Prevalence; MAP Kinase Gene; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Obesity; Oxidative Phosphorylation; Pathology; Persons; Phosphorylation; Phosphorylation Site; Physiological; Physiological Processes; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Promoter Regions; Proteins; RNA; RNA Polymerase II; Receptor Signaling; Regulation; Reporting; Resolution; Risk Factors; Rodent; Role; Scheme; Signal Induction; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Structure of beta Cell of islet; System; Techniques; Testing; Therapeutic; Thermogenesis; Trans-Activators; Transcriptional Regulation; Triglycerides; United States; Variant; Zinc Fingers; cell type; chromatin remodeling; comparative; computerized tools; current pandemic; epigenetic regulation; genome-wide; genomic data; improved; in vivo; islet; mRNA Expression; metabolic phenotype; mortality; novel; novel therapeutic intervention; overexpression; p38 Mitogen Activated Protein Kinase; phosphoproteomics; prevent; programs; promoter; protein expression; recruit; response; senescence; severe COVID-19; therapeutic target; transcription factor; transcriptome sequencing; uncoupling protein 1

Project Summary/Abstract Obesity and its metabolic sequelae are rapidly increasing in the United States and worldwide, leading to high morbidity and mortality in type 2 diabetes, cardiovascular disease, and certain cancer. Under the current pandemic, obesity has been recognized as a key risk factor for severe COVID-19. Central to these pathologies is adipose tissue. There are functionally distinct types of adipose tissue. White adipose tissue is the primary site of the triglyceride storehouse. In contrast, thermogenic fat, which consists of classical brown adipose tissue (BAT) and inducible beige/brite adipocytes, concentrates on thermogenic energy expenditure. It has been recently reported that people with BAT have a significantly lower prevalence of cardiometabolic diseases, highlighting the metabolic benefits and therapeutic potential of BAT in humans. To make the therapeutics possible, improved knowledge of the regulation of thermogenic adipocytes is urgently needed. The thermogenic function of brown and beige adipocytes are coordinately regulated by specific transcriptional and epigenetic regulators. While transcription of the thermogenic gene uncoupling protein 1 (Ucp1) in response to beta-adrenergic stimulation has been broadly studied, little is known about how histone positioning and chromatin folding influences the expression of Ucp1 and other thermogenic genes. Using an unbiased CRISPR-based screen, we identified the histone variant H2A.Z and the LIM domaining-containing zinc-finger protein Crip2 as trans-acting factors recruited to the Ucp1 promoter/enhancer region by beta3-adrenergic receptor stimulation. Importantly, deletion of H2A.Z or Crip2 in mature brown adipocytes not only impeded Ucp1 transcription, but also reduced the expression of multiple thermogenic genes and led to impaired cellular thermogenesis. This proposal will determine the signaling events mediating the activation of Crip2 and H2A.Z deposition and the impact of Crip2 or H2A.Z deficiency in the cellular thermogenesis and bioenergetic profiles of thermogenic adipocytes murine and human origins. Since histone variants play an important role in determining chromatin remodeling, we will examine how Crip2-H2A.Z interaction influences chromatin architecture, thereby regulating thermogenic transcription and cellular respiration. To establish the physiological significance of Crip2 and H2A.Z in metabolic regulation, we will generate brown fat-specific Crip2 or H2A.Z knockout mice and thoroughly characterize their metabolic phenotypes. Completing the proposed studies will increase fundamental knowledge on the role of chromatin remodeling in the regulation of thermogenic program and pave ways to establish new therapeutic approaches for combating metabolic diseases.

项目摘要/摘要 在美国和全球，肥胖及其代谢后遗症正在迅速增加，导致高 2型糖尿病，心血管疾病和某些癌症的发病率和死亡率。在电流下 大流行，肥胖症已被认为是严重covid-19的关键危险因素。这些病理的中心 是脂肪组织。有功能不同的脂肪组织类型。白脂肪组织是主要的 甘油三酸酯仓库的地点。相反，由经典的棕色脂肪组成的热脂肪脂肪 组织（蝙蝠）和诱导米色/棕脂脂肪细胞，集中于热能量消耗。它有 最近有报道说，蝙蝠患者的心脏代谢疾病患病率明显降低， 强调蝙蝠在人类中的代谢益处和治疗潜力。做治疗学 可能需要提高对热脂肪细胞调节的知识。这 棕色和米色脂肪细胞的热功能由特定的转录和 表观遗传调节剂。而热基因解偶联蛋白1（UCP1）的转录是响应于 β-肾上腺素能刺激已经广泛研究，对组蛋白定位和 染色质折叠会影响UCP1和其他热基因的表达。使用公正 基于CRISPR的屏幕，我们确定了组蛋白变体H2A.Z和含LIM元素的锌指 蛋白质CRIP2作为通过beta3-肾上腺素能募集到UCP1启动子/增强子区域的跨作用因子 受体刺激。重要的是，成熟棕色脂肪细胞中H2A.Z或CRIP2的缺失不仅阻碍 UCP1转录，但也降低了多种热基因的表达，并导致细胞受损 热发生。该建议将确定介导CRIP2和H2A.Z激活的信号传导事件 CRIP2或H2A.Z缺乏症对细胞热发生和生物能谱的影响 热脂肪细胞鼠和人类起源。由于组蛋白变体在 确定染色质重塑，我们将研究CRIP2-H2A.Z相互作用如何影响染色质 结构，从而调节热转录和细胞呼吸。建立 CRIP2和H2A.Z在代谢调节中的生理意义，我们将产生棕色脂肪特异性CRIP2 或H2A.Z敲除小鼠，并彻底表征其代谢表型。完成建议 研究将增加有关染色质重塑在调节中的作用的基本知识 热计划和铺平方法来建立新的治疗方法来对抗代谢 疾病。