Dual Functions of TAF7L in Adipocyte Differentiation

The diverse transcriptional mechanisms governing cellular differentiation and development of mammalian tissue remains poorly understood. Here we report that TAF7L, a paralogue of TFIID subunit TAF7, is enriched in adipocytes and mouse white fat tissue (WAT). Depletion of TAF7L reduced adipocyte-specific gene expression and compromised adipocyte differentiation as well as WAT development. Ectopic expression of TAF7L in myoblasts reprograms these muscle precursors into adipocytes upon induction. Genome-wide mRNA-seq expression profiling and ChIP-seq binding studies confirmed that TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARγ at enhancers and TBP/Pol II at core promoters. In vitro binding studies confirmed that TAF7L forms complexes with both TBP and PPARγ. These findings suggest that TAF7L plays an integral role in adipocyte gene expression by targeting enhancers as a cofactor for PPARγ and promoters as a component of the core transcriptional machinery. Genome-wide mapping of TAF7L and additional factors, and mRNA-seq expression profiling prior to and following mouse adipocyte differentiation.

调控哺乳动物组织细胞分化与发育的多样转录调控机制，目前仍未得到充分阐释。本研究报道，TAF7L作为转录因子IID（TFIID）亚基TAF7的旁系同源蛋白，在脂肪细胞（adipocytes）与小鼠白色脂肪组织（WAT）中富集表达。敲低TAF7L会降低脂肪细胞特异性基因的表达，并损害脂肪细胞分化与WAT发育过程。在成肌细胞（myoblasts）中异位表达TAF7L，可在诱导条件下将这些肌肉前体细胞重编程为脂肪细胞。全基因组mRNA测序（mRNA-seq）表达谱分析与染色质免疫沉淀测序（ChIP-seq）结合实验证实，TAF7L通过双重机制激活脂肪细胞特异性基因：它可在增强子（enhancers）区域与过氧化物酶体增殖物激活受体γ（PPARγ）结合，同时在核心启动子（core promoters）区域与TATA盒结合蛋白（TBP）/RNA聚合酶II（Pol II）相互作用。体外结合实验证实，TAF7L可与TBP及PPARγ分别形成复合物。上述研究结果表明，TAF7L作为PPARγ的辅助因子靶向增强子，并作为核心转录机器的组分作用于启动子，从而在脂肪细胞基因表达中发挥不可或缺的整合作用。本数据集涵盖小鼠脂肪细胞分化前后的TAF7L及其他相关因子的全基因组定位数据，以及mRNA-seq表达谱数据。