Novel transcriptional regulators for thermogenic program
产热程序的新型转录调节因子
基本信息
- 批准号:10318623
- 负责人:
- 金额:$ 37.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3T3-L1 CellsATAC-seqAblationAddressAdipose tissueAdrenergic AgentsAdultAffinity ChromatographyBindingBiologicalBiological AssayBiologyBody TemperatureBrown FatCRISPR/Cas technologyCellsChIP-seqChromatinChronic DiseaseCre driverCyclic AMP-Dependent Protein KinasesDiabetes MellitusDisease ManagementEMSAEnergy MetabolismEpidemicEpigenetic ProcessFamilyFutureGene ExpressionGenerationsGenesGenetic TranscriptionGlucoseGoalsHealthHomeostasisInsulinInsulin ResistanceKnockout MiceLibrariesMAP Kinase GeneMetabolic syndromeMethodsMethyltransferaseMolecularMorphologyMusMutateNon-Insulin-Dependent Diabetes MellitusObesityOrganPathway interactionsPatternPhosphorylationPhysiologicalPhysiologyPreventionPromoter RegionsProteinsRNA BindingRNA Recognition MotifRegulationReporterReportingResearchResistanceRespirationRoleSystemTestingTherapeuticThermogenesisTissuesTranscriptional ActivationTransgenic MiceZinc FingersbZIP Domaincofactorcombatdiabetes controldiet-induced obesityepigenetic regulationgain of functiongenome-widehistone methyltransferaseimprovedin vivoinhibitorinterestloss of functionmethylation patternmouse modelmutantnew therapeutic targetnovelobesity treatmentoverexpressionp38 Mitogen Activated Protein Kinasepri-miRNAprogramspromoterscreeningtranscription factortranscriptome sequencing
项目摘要
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.
肥胖是过量白色脂肪组织(WAT)的积累,与2型糖尿病和其他慢性疾病有关,并已成为一种流行病。WAT主要是一个能量储存器官,棕色脂肪组织(BAT)通过UCP1耗散能量产生热量来维持体温。随着成人中BAT/BAT样组织的识别,增加BAT或BAT活性可能会对抗肥胖。通过筛选已知的和推测的可以激活UCP1启动子的转录因子库,我们最近发现了一种属于C3H锌指家族的蛋白质,它可以强有力地激活UCP1和其他产热基因。该转录因子在BAT和WAT中富集,并在冷暴露时被诱导。我们通过EMSA和SELEX以及ChIP检测到该C3H因子在UCP1和其他BAT基因的启动子区域结合。CRISPR-Cas9系统消融培养BAT细胞,抑制UCP1等靶基因,减少解偶联呼吸。此外,小鼠脂肪组织中的过表达增加了能量消耗,伴随对饮食诱导的肥胖的抵抗,而脂肪组织的消融促进了肥胖和胰岛素抵抗。为了进一步研究该因子的功能,通过TAP-Mass - spec分析,我们确定了一种组蛋白甲基转移酶,我们发现它相互作用并协同起作用。在小鼠中,这种表观遗传因子的脂肪特异性消融也减少了促进肥胖的能量消耗。我们的目标是了解这种新的C3H转录因子及其相互作用蛋白在产热基因程序和产热中的分子机制和生理意义。目的1是研究这种C3H因子在激活UCP1启动子中的功能,并研究其全基因组靶点。目的2是研究其相互作用的辅助因子在产热基因程序的表观遗传调控中的关系和功能。最后,目的3是通过小鼠的功能增减研究,研究该C3H因子及其辅助因子在体内的作用及其在产热和肥胖中的关系。我们的研究将有助于更好地理解产热程序,并可能为未来开发有效的肥胖治疗方法提供目标。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 影响因子:0
- 作者:Yi D;Nguyen HP;Sul HS
- 通讯作者:Sul HS
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{{ truncateString('Hei Sook Sul', 18)}}的其他基金
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10713364 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10629810 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10396337 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10502853 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10357927 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Brown adipose NADH oxidase for thermogenesis
棕色脂肪 NADH 氧化酶用于产热
- 批准号:
10579854 - 财政年份:2020
- 资助金额:
$ 37.82万 - 项目类别:
Pref-1 receptor: Identification and characterization in inhibiting adipogenesis
Pref-1 受体:抑制脂肪生成的鉴定和表征
- 批准号:
10689082 - 财政年份:2019
- 资助金额:
$ 37.82万 - 项目类别:
Pref-1 receptor: Identification and characterization in inhibiting adipogenesis
Pref-1 受体:抑制脂肪生成的鉴定和表征
- 批准号:
9905913 - 财政年份:2019
- 资助金额:
$ 37.82万 - 项目类别:
Pref-1 receptor: Identification and characterization in inhibiting adipogenesis
Pref-1 受体:抑制脂肪生成的鉴定和表征
- 批准号:
10241438 - 财政年份:2019
- 资助金额:
$ 37.82万 - 项目类别:
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