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.

项目总结/摘要 肥胖及其代谢后遗症在美国和世界范围内迅速增加，导致高死亡率。 2型糖尿病、心血管疾病和某些癌症的发病率和死亡率。根据现行 在大流行期间，肥胖被认为是严重COVID-19的关键风险因素。这些疾病的核心 是脂肪组织脂肪组织有功能不同的类型。白色脂肪组织是主要的 甘油三酯仓库的位置相反，产热脂肪，其中包括经典的棕色脂肪 组织（BAT）和可诱导的米色/棕色脂肪细胞，集中于产热能量消耗。它有 最近有报道称，拥有BAT的人心脏代谢疾病的患病率显着降低， 强调BAT在人类中的代谢益处和治疗潜力。为了使治疗方法 迫切需要对产热脂肪细胞的调节的可能的、改进的知识。的 棕色和米色脂肪细胞的产热功能由特定的转录和 表观遗传调节因子。而产热基因解偶联蛋白1（Ucp 1）的转录则是对 β-肾上腺素能刺激已被广泛研究，但对组蛋白如何定位和 染色质折叠影响Ucp 1和其他产热基因的表达。用无偏差 在基于CRISPR的筛选中，我们鉴定了组蛋白变体H2A.Z和含有LIM结构域的锌指蛋白。 蛋白Crip 2作为反式作用因子被β 3-肾上腺素能受体募集到Ucp 1启动子/增强子区域 受体刺激重要的是，成熟棕色脂肪细胞中H2A.Z或Crip 2的缺失不仅阻碍了 Ucp 1转录，但也减少了多个产热基因的表达，并导致受损的细胞 产热作用该提议将确定介导Crip 2和H2A.Z活化的信号传导事件。 沉积和Crip 2或H2A.Z缺乏对细胞产热和生物能谱的影响 小鼠和人类来源的产热脂肪细胞。由于组蛋白变体在 为了确定染色质重塑，我们将研究Crip 2-H2A.Z相互作用如何影响染色质 结构，从而调节产热转录和细胞呼吸。建立 Crip 2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Crip 2 或H2A.Z敲除小鼠，并彻底表征其代谢表型。完成所提出的 这些研究将增加对染色质重塑在调节细胞凋亡中作用的基础知识。 产热计划，并为建立新的治疗方法，以对抗代谢 疾病