Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States.
The Broad Institute of MIT and Harvard, Cambridge, United States.
Elife. 2017 May 24;6:e20937. doi: 10.7554/eLife.20937.
Embryonic stem cells co-express Oct4 and Oct1, a related protein with similar DNA-binding specificity. To study the role of Oct1 in ESC pluripotency and transcriptional control, we constructed germline and inducible-conditional Oct1-deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal and growth but manifest defects upon differentiation. They fail to form beating cardiomyocytes, generate neurons poorly, form small, poorly differentiated teratomas, and cannot generate chimeric mice. Upon RA-mediated differentiation, Oct1-deficient cells induce lineage-appropriate developmentally poised genes poorly while lineage-inappropriate genes, including extra-embryonic genes, are aberrantly expressed. In ESCs, Oct1 co-occupies a specific set of targets with Oct4, but does not occupy differentially expressed developmental targets. Instead, Oct1 occupies these targets as cells differentiate and Oct4 declines. These results identify a dynamic interplay between Oct1 and Oct4, in particular during the critical window immediately after loss of pluripotency when cells make the earliest developmental fate decisions.
胚胎干细胞共同表达 Oct4 和 Oct1，一种与类似 DNA 结合特异性的相关蛋白。为了研究 Oct1 在 ESC 多能性和转录控制中的作用，我们构建了生殖系和诱导条件性 Oct1 缺陷型 ESC 系。缺乏 Oct1 的 ESC 表现出正常的外观、自我更新和生长，但在分化时表现出缺陷。它们不能形成跳动的心肌细胞，生成神经元的能力差，形成小而分化不良的畸胎瘤，并且不能生成嵌合小鼠。在 RA 介导的分化过程中，Oct1 缺陷型细胞诱导谱系适当的发育性基因的能力较差，而谱系不适当的基因，包括胚外基因，则异常表达。在 ESC 中，Oct1 与 Oct4 共同占据一组特定的靶标，但不占据差异表达的发育靶标。相反，随着细胞分化和 Oct4 下降，Oct1 占据这些靶标。这些结果表明 Oct1 和 Oct4 之间存在动态相互作用，特别是在失去多能性后细胞做出最早的发育命运决定的关键窗口期间。
