TRIM33在表观遗传水平上对TGF-β信号通路的调控

项目名称： TRIM33在表观遗传水平上对TGF-β信号通路的调控

项目编号： No.31471229

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 郗乔然

作者单位： 清华大学

项目金额： 110万元

中文摘要： TGF-β超家族在胚胎发育，组织稳态，成体免疫及伤口修复中起着中心调控作用。信号通路调控的核心是基因转录调控。TRIM33是TGF-β通路中调控基因转录的关键成员。研究表明，在早期小鼠胚胎干细胞中，TGF-β信号通路通过TRIM33-Smad2/3利用待激发的组蛋白标记H3K9me3来调控中内胚层调节子Gsc和Mixl1的表达，以此来诱导分化。但是，在表观遗传水平上TGF-β通过TRIM33-Smad2/3进行分化调控的具体机制及全基因组范围内的靶基因和调控位点，及在癌细胞内这些调控是如何中断的都未获得十分清楚的的解析。我们将鉴定存在于中内胚层已分化细胞内的TRIM33-Smad2/3的全部靶基因及基因组内潜在的调节性元件。通过鉴定和TRIM33作用的辅因子，阐明TRIM33-Smad2/3全局性促进中内胚层分化的机制，从而加深对TGF-β相关疾病特别是肿瘤和发育系统疾病的理解。

中文关键词： TGF-β信号转导；TRIM33；表观遗传学；胚胎干细胞；转录调控

英文摘要： The transforming growth factor (TGF-β)family plays major roles in embryo development, tissue homeostasis, adult immunity, and wound repair. Regulation of gene expression is central to all these effects. We have reported that TGF-β signals use the poised histone mark H3K9me3 to trigger differentiation of murine embryonic stem cells through TRIM33-Smad2/3. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. TRIM33-Smad2/3 binds the histone marks H3K9me3 and K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. Binding is through the PHD-Bromo cassette of TRIM33.But, how the signal pathway is regulated through TRIM33-Smad2/3 epigenetically, how Smads gain access to master differentiation genes in stem cells, and how these processes are disrupted in cancer remain poorly understood. In this proposed study, I will identify the entire set of target genes of TRIM33-Smad2/3 in differentiated mesendoderm cells and its potential regulatory elements in the genome. By identifying co-factors that associate with TRIM33 I will elucidate the mechanism by which TRIM33-Smad2/3 epigenetically promote mesendoderm differentiation. In addition, I will investigate how TRIM33 helps the cooperation between TGF-β and Wnt pathways during mesendoderm differentiation.

英文关键词： TGF-β signaling;TRIM33;epigenetics;embryonic stem cell;transcription regulation