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/文摘