Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095-7073, USA.
EMBO J. 2013 May 15;32(10):1393-408. doi: 10.1038/emboj.2013.78. Epub 2013 Apr 12.
Stem cell differentiation depends on transcriptional activation driven by lineage-specific regulators as well as changes in chromatin organization. However, the coordination of these events is poorly understood. Here, we show that T-box proteins team up with chromatin modifying enzymes to drive the expression of the key lineage regulator, Eomes during endodermal differentiation of embryonic stem (ES) cells. The Eomes locus is maintained in a transcriptionally poised configuration in ES cells. During early differentiation steps, the ES cell factor Tbx3 associates with the histone demethylase Jmjd3 at the enhancer element of the Eomes locus to allow enhancer-promoter interactions. This spatial reorganization of the chromatin primes the cells to respond to Activin signalling, which promotes the binding of Jmjd3 and Eomes to its own bivalent promoter region to further stimulate Eomes expression in a positive feedback loop. In addition, Eomes activates a transcriptional network of core regulators of endodermal differentiation. Our results demonstrate that Jmjd3 sequentially associates with two T-box factors, Tbx3 and Eomes to drive stem cell differentiation towards the definitive endoderm lineage.
干细胞的分化依赖于谱系特异性调控因子驱动的转录激活以及染色质组织的变化。然而，这些事件的协调机制还知之甚少。在这里，我们发现 T 盒蛋白与染色质修饰酶协同作用，在胚胎干细胞（ES 细胞）的内胚层分化过程中驱动关键谱系调控因子 Eomes 的表达。Eomes 基因座在 ES 细胞中保持在转录活跃的构象。在早期分化步骤中，ES 细胞因子 Tbx3 与组蛋白去甲基酶 Jmjd3 在内胚层分化过程中结合在 Eomes 基因座的增强子元件上，允许增强子-启动子相互作用。这种染色质的空间重组织使细胞能够对激活素信号做出反应，促进 Jmjd3 和 Eomes 与其自身的二价启动子区域结合，进一步在正反馈环中刺激 Eomes 的表达。此外，Eomes 激活了内胚层分化的核心调控因子的转录网络。我们的结果表明，Jmjd3 依次与两个 T 盒因子 Tbx3 和 Eomes 结合，驱动干细胞向确定的内胚层谱系分化。
