Thyroid Hormone Receptors in Health and Disease

健康和疾病中的甲状腺激素受体

基本信息

批准号：
9153499
负责人：
SHEUE-YANN CHENG
金额：
$ 72.66万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9153499
关键词：
Affect Binding Binding Sites Biological Process ChIP-seq Chromatin Complex Constipation DNA Sequence DNase I hypersensitive sites sequencing Data Development Differentiation and Growth Disease Exhibits Family Feedback Gene Expression Regulation Gene Targeting Genetic Transcription Goals Growth Health Hormones Hypothalamic structure Hypothyroidism Individual Ligands Liver Maps Mediating Modeling Molecular Monitor Mus Mutation Patients Pituitary Gland Process Protein Isoforms Reporting Resistance Serum THRA gene THRB gene Thyroid Gland Thyroid Hormone Receptor Thyroid Hormones Thyrotropin Transcriptional Activation Transcriptional Regulation Triiodothyronine Work base chromatin remodeling genome-wide hormone response element in vivo insight mouse model mutant promoter receptor skeletal dysplasia steroid hormone receptor transcription factor

项目摘要

Transcription activation by the thyroid hormone receptor through ligand dependent receptor recruitment and chromatin remodeling. As a first step toward understanding how TR mutants act in vivo differently from the WT TR genome-wide, we first identified the cistrome of endogenous TRbeta1 and probed the chromatin landscape in the regulation of transcription by TR in the mouse liver. The current understanding of TR transcription regulation has been based on a bimodal switch model. In this model, the unliganded TR forms chromatin bound stable complexes with transcriptional co-repressors to repress transcription. Binding of T3 dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Using ChIP-seq against endogenous TRbeta1, we found that in addition to T3-independent TRbeta1 occupancy, there is considerable T3-induced TRbeta1 recruitment to chromatin associated with chromatin remodeling to activate gene transcription. DNase I hypersensitive site sequencing (DNase-seq) data provide little evidence for TRbeta1 footprints either in the absence or presence of T3. These results suggest the unliganded TR engagement with repressive complexes on chromatin, similar to activating receptor complexes, is a highly dynamic process. The action of TR now appears more aligned with well-developed models for steroid hormone receptor action. This new model of T3 action represents a significant step toward a better understanding of mechanisms of gene regulation by this important hormone. Importantly, the present work has facilitated the studies for gaining molecular insights into the basis of TR mutations in disease.

通过配体依赖受体募集和染色质重塑，甲状腺激素受体的转录激活。作为了解Tr突变体在体内的作用的第一步，与WT TR基因组的作用不同，我们首先鉴定了内源性TRBETA1的Cistrome，并在小鼠肝脏中TR调节转录时探测了染色质景观。当前对TR转录调节的理解是基于双峰开关模型。在此模型中，无配合的TR与转录共抑制剂形成染色质结合的稳定复合物，以抑制转录。 T3解离的结合可以使共抑制剂促进共激活因子激活转录。使用chip-seq针对内源性TRBETA1，我们发现除了与T3无关的TRBETA1占用率外，T3诱导的TRBETA1募集到与染色质重塑相关的染色质以激活基因转录相关的染色质。 DNase I超敏位点测序（DNASE-SEQ）数据在不存在或存在T3的情况下几乎没有证据表明TRBETA1足迹。这些结果表明，与激活受体复合物类似的染色质上的无抗抑制性复合物的无配合的TR参与是一个高度动态的过程。现在，TR的作用似乎与开发的类固醇激素受体作用的模型更加一致。 T3作用的新模型是朝着更好地理解这种重要激素对基因调节机制的重要一步。重要的是，目前的工作促进了对疾病中TR突变基础的分子见解的研究。