Liu Guo-You, Zhao Guang-Nian, Chen Xiao-Feng, Hao De-Long, Zhao Xiang, Lv Xiang, Liu De-Pei
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P.R. China.
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P.R. China
Nucleic Acids Res. 2016 Apr 7;44(6):2613-27. doi: 10.1093/nar/gkv1315. Epub 2015 Nov 28.
The Hox genes encode transcription factors that determine embryonic pattern formation. In embryonic stem cells, the Hox genes are silenced by PRC2. Recent studies have reported a role for long noncoding RNAs in PRC2 recruitment in vertebrates. However, little is known about how PRC2 is recruited to the Hox genes in ESCs. Here, we used stable knockdown and knockout strategies to characterize the function of the long noncoding RNAGm15055 in the regulation of Hoxa genes in mouse ESCs. We found that Gm15055 is highly expressed in mESCs and its expression is maintained by OCT4.Gm15055 represses Hoxa gene expression by recruiting PRC2 to the cluster and maintaining the H3K27me3 modification on Hoxa promoters. A chromosome conformation capture assay revealed the close physical association of the Gm15055 locus to multiple sites at the Hoxa gene cluster in mESCs, which may facilitate the in cis targeting of Gm15055RNA to the Hoxa genes. Furthermore, an OCT4-responsive positive cis-regulatory element is found in the Gm15055 gene locus, which potentially regulates both Gm15055 itself and the Hoxa gene activation. This study suggests how PRC2 is recruited to the Hoxa locus in mESCs, and implies an elaborate mechanism for Hoxa gene regulation in mESCs.
Hox基因编码决定胚胎模式形成的转录因子。在胚胎干细胞中，Hox基因被PRC2沉默。最近的研究报道了长链非编码RNA在脊椎动物PRC2招募中的作用。然而，关于PRC2如何被招募到胚胎干细胞中的Hox基因上，我们知之甚少。在这里，我们使用稳定的敲低和敲除策略来表征长链非编码RNA Gm15055在小鼠胚胎干细胞中对Hoxa基因调控的功能。我们发现Gm15055在小鼠胚胎干细胞中高度表达，其表达由OCT4维持。Gm15055通过将PRC2招募到基因簇并维持Hoxa启动子上的H3K27me3修饰来抑制Hoxa基因表达。染色体构象捕获分析揭示了Gm15055基因座与小鼠胚胎干细胞中Hoxa基因簇多个位点的紧密物理关联，这可能有助于Gm15055 RNA顺式靶向Hoxa基因。此外，在Gm15055基因座中发现了一个OCT4反应性正向顺式调节元件，它可能同时调节Gm15055本身和Hoxa基因的激活。这项研究揭示了PRC2如何被招募到小鼠胚胎干细胞中的Hoxa基因座，并暗示了小鼠胚胎干细胞中Hoxa基因调控的一种精细机制。
