A distal enhancer maintaining Hoxa1 expression orchestrates retinoic acid-induced early ESCs differentiation
A distal enhancer maintaining Hoxa1 expression orchestrates retinoic acid-induced early ESCs differentiation
复制标题
维持 Hoxa1 表达的远端增强子协调视黄酸诱导的早期 ESC 分化
DOI：
10.1093/nar/gkz482
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发表时间：
2019-07-26
影响因子：
14.9
通讯作者：
Lu, Wange
中科院分区：
文献类型：
--
作者：
Su, Guangsong;Guo, Dianhao;Lu, Wange
视黄酸 (RA) 诱导胚胎干细胞 (ESC) 快速分化，部分原因是激活转录因子 Hoxa1 的表达，该因子调节促进 ESC 分化的下游靶基因。然而，RA 诱导 Hoxa1 表达和 ESC 早期分化的机制仍然很大程度上未知。在这里，我们确定了一个通过远程染色质环与 Hoxa1 基因座相互作用的远端增强子。增强子缺失显着抑制 RA 诱导的 Hoxa1 和内胚层主控基因（如 Gata4 和 Gata6）的表达。转录组分析显示，Hoxa1 增强子敲除细胞中 RA 诱导的早期 ESC 分化被阻断，表明需要增强子。 Hoxa1表达的恢复部分挽救了大约40%在增强子删除后表达发生变化的基因的表达水平，并且大约18%的这些挽救基因的启动子直接与Hoxa1结合。我们的数据表明，远端增强子通过长程染色质环维持 Hoxa1 表达，并且 Hoxa1 直接调节下游靶基因表达，然后协调 RA 诱导的 ESC 早期分化。这一发现揭示了一种新型增强子调节 RA 诱导的 Hoxa 基因表达和早期 ESC 分化的机制。
Retinoic acid (RA) induces rapid differentiation of embryonic stem cells (ESCs), partly by activating expression of the transcription factor Hoxa1, which regulates downstream target genes that promote ESCs differentiation. However, mechanisms of RA-induced Hoxa1 expression and ESCs early differentiation remain largely unknown. Here, we identify a distal enhancer interacting with the Hoxa1 locus through a long-range chromatin loop. Enhancer deletion significantly inhibited expression of RA-induced Hoxa1 and endoderm master control genes such as Gata4 and Gata6. Transcriptome analysis revealed that RA-induced early ESCs differentiation was blocked in Hoxa1 enhancer knockout cells, suggesting a requirement for the enhancer. Restoration of Hoxa1 expression partly rescued expression levels of similar to 40% of genes whose expression changed following enhancer deletion, and similar to 18% of promoters of those rescued genes were directly bound by Hoxa1. Our data show that a distal enhancer maintains Hoxa1 expression through long-range chromatin loop and that Hoxa1 directly regulates downstream target genes expression and then orchestrates RA-induced early differentiation of ESCs. This discovery reveals mechanisms of a novel enhancer regulating RA-induced Hoxa genes expression and early ESCs differentiation.