Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell. 2011 Sep 30;147(1):120-31. doi: 10.1016/j.cell.2011.08.038.
The transcriptional activators Oct4, Sox2, and Nanog cooperate with a wide array of cofactors to orchestrate an embryonic stem (ES) cell-specific gene expression program that forms the molecular basis of pluripotency. Here, we report using an unbiased in vitro transcription-biochemical complementation assay to discover a multisubunit stem cell coactivator complex (SCC) that is selectively required for the synergistic activation of the Nanog gene by Oct4 and Sox2. Purification, identification, and reconstitution of SCC revealed this coactivator to be the trimeric XPC-nucleotide excision repair complex. SCC interacts directly with Oct4 and Sox2 and is recruited to the Nanog and Oct4 promoters as well as a majority of genomic regions that are occupied by Oct4 and Sox2. Depletion of SCC/XPC compromised both pluripotency in ES cells and somatic cell reprogramming of fibroblasts to induced pluripotent stem (iPS) cells. This study identifies a transcriptional coactivator with diversified functions in maintaining ES cell pluripotency and safeguarding genome integrity.
转录激活因子 Oct4、Sox2 和 Nanog 与广泛的辅助因子合作，协调胚胎干细胞（ES 细胞）特异性基因表达程序，形成多能性的分子基础。在这里，我们报告使用一种无偏见的体外转录生化互补测定法来发现一个多亚基干细胞共激活复合物（SCC），该复合物对于 Oct4 和 Sox2 协同激活 Nanog 基因是选择性必需的。SCC 的纯化、鉴定和重建表明，这种共激活因子是三聚体 XPC-核苷酸切除修复复合物。SCC 与 Oct4 和 Sox2 直接相互作用，并被募集到 Nanog 和 Oct4 启动子以及 Oct4 和 Sox2 占据的大多数基因组区域。SCC/XPC 的耗竭损害了 ES 细胞的多能性和体细胞重编程为诱导多能干细胞（iPS 细胞）。这项研究鉴定了一种在维持 ES 细胞多能性和保护基因组完整性方面具有多样化功能的转录共激活因子。
