Transcriptional repression of Nanog is an important hallmark of stem cell differentiation. Chromatin modifications have been linked to the epigenetic profile of the Nanog gene, but whether chromatin organization actually plays a causal role in Nanog regulation is still unclear. Here, we report that the formation of a chromatin loop in the Nanog locus is concomitant to its transcriptional downregulation during human NTERA-2 cell differentiation. We found that two Alu elements flanking the Nanog gene were bound by the aryl hydrocarbon receptor (AhR) and the insulator protein CTCF during cell differentiation. Such binding altered the profile of repressive histone modifications near Nanog likely leading to gene insulation through the formation of a chromatin loop between the two Alu elements. Using a dCAS9-guided proteomic screening, we found that interaction of the histone methyltransferase PRMT1 and the chromatin assembly factor CHAF1B with the Alu elements flanking Nanog was required for chromatin loop formation and Nanog repression. Therefore, our results uncover a chromatin-driven, retrotransposon-regulated mechanism for the control of Nanog expression during cell differentiation.

中文翻译：

---

Alu逆转座子通过芳基烃受体通过区域染色质构象的动态变化调节Nanog表达。

Nanog的转录抑制是干细胞分化的重要标志。染色质修饰与Nanog基因的表观遗传特性有关，但是染色质组织是否实际上在Nanog调节中起着因果作用还不清楚。在这里，我们报告在Nanog基因座中染色质环的形成与其在人类NTERA-2细胞分化过程中的转录下调相伴。我们发现，在细胞分化过程中，Nanog基因两侧的两个Alu元素被芳烃受体（AhR）和绝缘蛋白CTCF结合。这种结合改变了Nanog附近的抑制性组蛋白修饰的轮廓，可能通过在两个Alu元件之间形成染色质环而导致基因绝缘。使用dCAS9指导的蛋白质组学筛选，我们发现，组蛋白甲基转移酶PRMT1和染色质装配因子CHAF1B与Nanog侧翼的Alu元素的相互作用是染色质环形成和Nanog抑制所必需的。因此，我们的结果揭示了染色质驱动的逆转录转座子调控的机制，用于控制细胞分化过程中Nanog的表达。