MicroRNA-26a induced by hypoxia targets HDAC6 in myogenic differentiation of embryonic stem cells.
MicroRNA-26a induced by hypoxia targets HDAC6 in myogenic differentiation of embryonic stem cells.
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DOI：
10.1093/nar/gkv088
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发表时间：
2015-02-27
影响因子：
14.9
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
Lee SW;Yang J;Kim SY;Jeong HK;Lee J;Kim WJ;Lee EJ;Kim HS
表观遗传调控对于维持胚胎干细胞(ESC)的多能性或启动分化的重要性被广泛接受。然而，其分子机制却知之甚少。我们最近报道了低氧微环境诱导胚胎干细胞分化。在本研究中，我们发现低氧反应的组蛋白脱乙酰酶6(HDAC6)对胚胎干细胞的肌源性分化具有重要的信号功能。HDAC6在低氧的ESCs或分化过程中表达下调。胚胎干细胞中HDAC6基因的敲除导致了包括Pax7在内的肌源性标志物的诱导。抑制HDAC6增加了核心组蛋白H3和H4的乙酰化，导致RNA聚合酶II与Pax7启动子的结合增强。HDAC6基因敲除细胞移植促进了体内肌肉再生。重要的是，低氧对HDAC6的下调不是通过缺氧下的主要转录调控因子HIF1α或HIF2α介导的，而是通过诱导直接针对HDAC6的3‘-非翻译区的microRNA-26a来实现的。HDAC6 3‘-UTR中microRNA-26a结合序列的点突变降低了荧光素酶报告基因的活性。综上所述，这些结果表明，分化的环境线索调节了表观遗传机制，并引导干细胞致力于特定的谱系。
The importance of epigenetic regulation for maintenance of embryonic stem cell (ESC) pluripotency or for initiation of differentiation is widely accepted. However, the molecular mechanisms are poorly understood. We recently reported that a hypoxic microenvironment induces ESC differentiation. In the present study, we found that hypoxia-responsive histone deacetylase 6 (HDAC6) performs an essential signaling function for myogenic differentiation of ESCs. HDAC6 was downregulated in hypoxic ESCs or during differentiation. A knock-down of HDAC6 in ESCs resulted in induction of myogenic markers, including Pax7. Suppression of HDAC6 increased acetylation of core histones H3 and H4, leading to enhanced binding of RNA polymerase II to the Pax7 promoter. Transplantation of HDAC6 knock-down cells facilitated muscle regeneration in vivo. Importantly, the downregulation of HDAC6 by hypoxia was not mediated by HIF1α or HIF2α, master transcription regulators under hypoxia, but by induction of microRNA-26a that directly targeted the 3′-untranslated region (3′-UTR) of HDAC6. A point mutation of the microRNA-26a-binding sequence in the HDAC6 3′-UTR diminished the luciferase reporter activity. Taken together, these results suggest that environmental cues of differentiation modulate the epigenetic machinery and guide stem cells to commit to a specific lineage.
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通讯作者：
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