Integrative Physiology of Thyroid Hormone Receptors and Nuclear Receptor Corepressors

甲状腺激素受体和核受体辅阻遏物的综合生理学

• 批准号: 10398852
• 负责人: MITCHELL A. LAZAR
• 金额: $ 53.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398852
• 关键词: Address; Affinity; Binding; Bioinformatics; Biological; Biological Models; Body Temperature; Brown Fat; Cardiovascular Diseases; Cell Nucleus; ChIP-seq; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA Sequence; Data; Dependence; Diabetes Mellitus; Energy Metabolism; Enhancers; Environment; Environmental Risk Factor; Enzymes; Epidemic; Epitopes; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; Goals; HDAC3 gene; Harvest; Hormones; Hyperthyroidism; IL4 gene; In Vitro; Inflammation; Knock-out; Kupffer Cells; Laboratories; Lead; Light; Liver; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methodology; Methods; Modeling; Multiprotein Complexes; Mus; Nuclear; Nuclear Receptors; Obesity; Overnutrition; Pathologic; Pathway interactions; Phenocopy; Physiological; Physiology; Proteins; Proteomics; Repression; Role; Set protein; Silencing Mediator of Retinoid Thyroid Receptor; Specificity; Structure; System; Systems Biology; Testing; Thyroid Function Tests; Thyroid Hormone Receptor; Thyroid Hormone Receptor Beta; Thyroid Hormones; Time; Tissues; Transcription Repressor; United States; Work; base; chromatin immunoprecipitation; cold temperature; environmental stressor; enzyme activity; epigenome; epigenomics; experimental study; genetic corepressor; global run on sequencing; in vivo; innovation; insight; knock-down; lipid metabolism; macrophage; metabolic phenotype; mouse model; mutant; next generation sequencing; novel; physiologic model; receptor function; response; transcription factor; transcriptome; transcriptome sequencing; uncoupling protein 1

PROJECT SUMMARY A major goal of this laboratory is to understand the mechanisms by which nuclear receptors (NRs) regulate gene expression and metabolism. Thyroid hormone receptors (TRs) are classical NRs that regulate lipid and energy metabolism. TRs switch from transcriptional repressors to activators in response to their cognate hormone. Repression is mediated by NR corepressors, NCoR and SMRT, which function in multiprotein complexes containing histone deacetylase 3 (HDAC3), whose catalytic activity requires direct interaction with NCoR/SMRT. However, recent studies suggest a more complex mechanism for TR repression. Further, the roles of NCoR/SMRT and HDAC3 in metabolism and inflammation are highly tissue-specific via mechanisms that remain to be understood. We have pioneered a systems approach that combines state-of-the-art in vivo "omics" approaches with genetic and environmental manipulations and metabolic phenotyping to unravel the complex mechanisms by which NRs, corepressors and HDAC3 control normal physiology and contribute to the pathophysiology of metabolic diseases. Specific Aim 1 is to determine the interactions and functions of thyroid hormone receptor beta on chromatin. The coregulator switch model of hormone action is largely based on in vitro experiments using artificial systems. By combining expertise in cistromics with quantitative proteomics by NEAT ChIP-MS (Nuclear Extraction Affinity Tag ChIP-mass spec) we will interrogate the hormone-dependent protein and genomic interactions of TR1to elucidate, for the first time, the in vivo protein interactions of TR and their physiological functions. Specific Aim 2 is to determine the physiological, tissue-specific functions of nuclear receptor corepressors. NCoR depletion phenocopies loss of HDAC3 in liver but not in brown adipose tissue (BAT). We will determine the basis of this difference by comparing and contrasting transcriptomes, cistromes, enhancer activities, and metabolic phenotypes upon cdeletion of HDAC3 and NCoR/SMRT. Specific Aim 3 is to determine the physiological, tissue-specific functions of HDAC3 and its enzyme activity. Catalytically inactive HDAC3 partially rescues the steatosis of livers lacking HDAC3 and, in macrophages, and can replace HDAC3 in controlling the LPS (M1) response but not the response to IL4 (M2). We will use a combination of NEAT ChIP-MS, cistromics, and enhancer quantitation in wild type, mutant, and knockout models to elucidate the transcription factors and protein partners underlying the gene-specific requirement for HDAC3 enzyme activity. The tissue specificity of HDAC3 interactions and enzyme activity will be addressed by comparing the results of NEAT ChIP-MS on endogenous epitope-tagged wild-type and catalytically inactive HDAC3 in liver, macrophages, and BAT. These innovative studies address major questions regarding the mechanisms of action of TRs, NR corepressors, and HDAC3 and will shed new light on the transcriptional and epigenomic control of key metabolic pathways, with the goal of gaining deeper insights into metabolic disorders such as obesity, diabetes, and cardiovascular disease, as well as cancer.

项目摘要 该实验室的一个主要目标是了解核受体（NR）调节的机制 基因表达和代谢。甲状腺激素受体（TR）是调节脂质和 能量代谢TRs从转录抑制子转换为激活子， 激素.抑制是由NR辅阻遏物NCoR和SMRT介导的，它们在多蛋白中起作用。 含有组蛋白脱乙酰基酶3（HDAC 3）的复合物，其催化活性需要与 NCoR/SMRT。然而，最近的研究表明TR抑制的机制更复杂。此夕h NCoR/SMRT和HDAC 3在代谢和炎症中的作用是高度组织特异性的， 这还有待理解。我们开创了一种系统方法，将最先进的体内 “组学”方法与遗传和环境操纵和代谢表型，以解开 NR、辅阻遏物和HDAC 3控制正常生理学并有助于促进细胞凋亡的复杂机制。 代谢性疾病的病理生理学具体目标1是确定的相互作用和功能， 染色质上的甲状腺激素受体β激素作用的辅调节子转换模型主要是 基于使用人工系统的体外实验。通过将顺式异构体的专业知识与定量 蛋白质组学NEAT ChIP-MS（核提取亲和标签ChIP-mass spec），我们将询问 TR β 1依赖的蛋白质和基因组相互作用首次阐明了体内蛋白质 TR的相互作用及其生理功能。具体目标2是确定生理， 核受体辅阻遏物的组织特异性功能。NCoR耗竭表型模拟HDAC 3的损失 在肝脏中，但不在棕色脂肪组织（BAT）中。我们将通过比较来确定这种差异的基础， 对比转录组、顺式组、增强子活性和cdeletion后的代谢表型， HDAC 3和NCoR/SMRT。具体目标3是确定的生理，组织特异性功能， HDAC 3及其酶活性。无催化活性的HDAC 3部分挽救缺乏脂肪变性的肝脏 HDAC 3和，在巨噬细胞中，可以取代HDAC 3控制LPS（M1）反应，但不能控制LPS（M1）反应。 对IL 4（M2）的反应。我们将使用NEAT ChIP-MS，cistrolavin和增强子定量的组合， 野生型、突变体和敲除模型，以阐明转录因子和蛋白质伴侣， HDAC 3酶活性的基因特异性要求。HDAC 3相互作用的组织特异性和 酶活性将通过比较NEAT ChIP-MS对内源性表位标记的 肝脏、巨噬细胞和BAT中的野生型和无催化活性的HDAC 3。这些创新研究涉及 关于TRs，NR辅阻遏物和HDAC 3的作用机制的主要问题，并将揭示新的 光的转录和表观基因组控制的关键代谢途径，以获得更深的目标 对肥胖、糖尿病、心血管疾病以及癌症等代谢紊乱的深入了解。

项目成果

Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue.

• DOI: 10.1073/pnas.2205276119
• 发表时间: 2022-08-16
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

A novel role for helix 12 of retinoid X receptor in regulating repression.

类视黄醇 X 受体螺旋 12 在调节抑制中的新作用。

• DOI: 10.1128/mcb.19.9.6448
• 发表时间: 1999
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Zhang,J;Hu,X;Lazar,MA
• 通讯作者: Lazar,MA

The unique C-termini of the thyroid hormone receptor variant, c-erbA alpha 2, and thyroid hormone receptor alpha 1 mediate different DNA-binding and heterodimerization properties.

甲状腺激素受体变体 c-erbA α 2 和甲状腺激素受体 α 1 的独特 C 末端介导不同的 DNA 结合和异二聚化特性。

• DOI: 10.1210/mend.6.5.1318505
• 发表时间: 1992
• 期刊: Molecular endocrinology (Baltimore, Md.)
• 作者: Katz,D;Berrodin,TJ;Lazar,MA
• 通讯作者: Lazar,MA

RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure.

• DOI: 10.1172/jci162309
• 发表时间: 2023-05-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Yamamoto, Tsunehisa;Maurya, Santosh K.;Pruzinsky, Elizabeth;Batmanov, Kirill;Xiao, Yang;Sulon, Sarah M.;Sakamoto, Tomoya;Wang, Yang;Lai, Ling;McDaid, Kendra S.;Shewale, Swapnil V.;Leone, Teresa C.;Koves, Timothy R.;Muoio, Deborah M.;Dierickx, Pieterjan;Lazar, Mitchell A.;Lewandowski, E. Douglas;Kelly, Daniel P.
• 通讯作者: Kelly, Daniel P.

Dissociating fatty liver and diabetes.

• DOI: 10.1016/j.tem.2012.09.005
• 发表时间: 2013-01
• 期刊: TRENDS IN ENDOCRINOLOGY AND METABOLISM
• 影响因子: 10.9
• 作者: Sun, Zheng;Lazar, Mitchell A.
• 通讯作者: Lazar, Mitchell A.