Novel transcriptional regulators for thermogenic program

产热程序的新型转录调节因子

• 批准号: 10318623
• 负责人: Hei Sook Sul
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-18 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318623
• 关键词: 3T3-L1 Cells; ATAC-seq; Ablation; Address; Adipose tissue; Adrenergic Agents; Adult; Affinity Chromatography; Binding; Biological; Biological Assay; Biology; Body Temperature; Brown Fat; CRISPR/Cas technology; Cells; ChIP-seq; Chromatin; Chronic Disease; Cre driver; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Disease Management; EMSA; Energy Metabolism; Epidemic; Epigenetic Process; Family; Future; Gene Expression; Generations; Genes; Genetic Transcription; Glucose; Goals; Health; Homeostasis; Insulin; Insulin Resistance; Knockout Mice; Libraries; MAP Kinase Gene; Metabolic syndrome; Methods; Methyltransferase; Molecular; Morphology; Mus; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; Pattern; Phosphorylation; Physiological; Physiology; Prevention; Promoter Regions; Proteins; RNA Binding; RNA Recognition Motif; Regulation; Reporter; Reporting; Research; Resistance; Respiration; Role; System; Testing; Therapeutic; Thermogenesis; Tissues; Transcriptional Activation; Transgenic Mice; Zinc Fingers; bZIP Domain; cofactor; combat; diabetes control; diet-induced obesity; epigenetic regulation; gain of function; genome-wide; histone methyltransferase; improved; in vivo; inhibitor; interest; loss of function; methylation pattern; mouse model; mutant; new therapeutic target; novel; obesity treatment; overexpression; p38 Mitogen Activated Protein Kinase; pri-miRNA; programs; promoter; screening; transcription factor; transcriptome sequencing

Obesity, the accumulation of excess white adipose tissue (WAT), is associated with type 2 diabetes and other chronic diseases and has become an epidemic. While WAT is primarily an energy storage organ, brown adipose tissue (BAT) dissipates energy for heat generation via UCP1 to maintain body temperature. With the recognition of BAT/BAT-like tissues in human adults, increasing BAT or BAT activity may combat obesity. By screening a library of known and putative transcription factors that can activate UCP1 promoter, we recently have identified a largely uncharacterized a protein belonging to C3H zinc finger family, that can robustly activate UCP1 and other thermogenic genes. This transcription factor is enriched in BAT versus WAT and is induced upon cold-exposure. We detected binding of this C3H factor at the promoter regions of UCP1 and other BAT genes by EMSA and SELEX as well as by ChIP. Ablation by CRISPR-Cas9 system in BAT cells in culture suppressed UCP1 and other target genes to reduce uncoupled respiration. Moreover, overexpression in adipose tissue in mice increased energy expenditure to accompany resistance to diet- induced obesity, whereas ablation in adipose tissue promoted obesity and insulin resistance. To further examine the function of this factor, by TAP-Mass spec analysis, we identified a histone methyltransferase, which we found to interact and function synergistically. Adipose specific ablation of this epigenetic factor in mice also decreased energy expenditure promoting obesity. Our goal is to understand the molecular mechanisms and physiological significance of this new C3H transcription factor and its interacting protein for the thermogenic gene program and thermogenesis: Aim 1 is to investigate the function of this C3H factor in activating UCP1 promoter and study its genome-wide targets. Aim 2 is to examine the relationship and function of its interacting cofactor in epigenetic regulation of the thermogenic gene program. Finally, Aim 3 is to study the in vivo role of this C3H factor, its cofactor and their relationship in thermogenesis and adiposity by gain- and loss-of function studies in mice. Our research will help better understand the thermogenic program and may provide targets for developing effective obesity therapeutics in the future.

肥胖，多余的白脂肪组织（WAT）的积累与2型糖尿病和其他慢性疾病有关，并且已经成为流行病。虽然WAT主要是一种能量器官，但棕色脂肪组织（BAT）通过UCP1消散了热量的能量，以维持体温。随着人类成年人的蝙蝠/蝙蝠状组织的识别，蝙蝠或蝙蝠活性的增加可能会抗击肥胖。通过筛选可以激活UCP1启动子的已知和推定转录因子的库，我们最近已经确定了一个属于C3H锌指家族的蛋白质，可以强烈激活UCP1和其他热基因。该转录因子富含BAT与WAT，并在冷暴露后诱导。我们通过EMSA和SELEX以及芯片检测到该C3H因子在UCP1和其他BAT基因的启动子区域的结合。 CRISPR-CAS9系统在培养物中的烧蚀抑制了UCP1和其他靶基因，以减少未偶联的呼吸。此外，小鼠脂肪组织中的过表达增加了能量消耗，伴随着对饮食诱发的肥胖的耐药性，而脂肪组织的消融促进了肥胖和胰岛素抵抗。为了进一步检查该因素的功能，通过Tap-Mass Spec分析，我们鉴定了一个组蛋白甲基转移酶，我们发现该酶是通过协同作用的。小鼠中这种表观遗传因素的脂肪特异性消融也减少了促进肥胖症的能量消耗。我们的目标是了解这种新的C3H转录因子的分子机制和生理意义及其对热基因程序和热生成的相互作用蛋白质的相互作用蛋白：目标1是研究该C3H因子激活UCP1启动子并研究其全基因组靶标的功能。目的2是检查其相互作用辅助因子在热基因程序表观遗传调节中的关系和功能。最后，目标3是研究该C3H因子的体内作用，其辅助因子及其在小鼠中的功能丧失研究中的生热和肥胖中的关系。我们的研究将有助于更好地理解热源计划，并可能为未来开发有效的肥胖治疗剂提供目标。

项目成果

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes.

• DOI: 10.7554/elife.59990
• 发表时间: 2020-10-27
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yi D;Nguyen HP;Dinh J;Viscarra JA;Xie Y;Lin F;Zhu M;Dempersmier JM;Wang Y;Sul HS
• 通讯作者: Sul HS

Epigenetic dynamics of the thermogenic gene program of adipocytes.

• DOI: 10.1042/bcj20190599
• 发表时间: 2020-03-27
• 期刊: The Biochemical journal
• 作者: Yi D;Nguyen HP;Sul HS
• 通讯作者: Sul HS