PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.
PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.
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DOI：
10.1016/j.celrep.2015.07.053
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发表时间：
2015-09-01
期刊：
影响因子：
8.8
通讯作者：
Orkin SH
中科院分区：
文献类型：
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作者：
Das PP;Hendrix DA;Apostolou E;Buchner AH;Canver MC;Beyaz S;Ljuboja D;Kuintzle R;Kim W;Karnik R;Shao Z;Xie H;Xu J;De Los Angeles A;Zhang Y;Choe J;Jun DL;Shen X;Gregory RI;Daley GQ;Meissner A;Kellis M;Hochedlinger K;Kim J;Orkin SH
多梳抑制复合物2（PRC 2）功能和DNA甲基化（DNAme）通常与基因抑制相关。在这里，我们表明PRC 2是维持来自Gtl 2-Rian-Mirg基因座的母体microRNA（miRNA）和长非编码RNA（lncRNA）表达所必需的，这对于iPSC的完全多能性是必需的。在不存在PRC 2的情况下，由于在基因间差异甲基化区域（IG-DMR）处获得DNA甲基化，整个基因座变得转录抑制。此外，我们证明IG-DMR作为母体Gtl 2-Rian-Mirg基因座的增强子。机制研究揭示，PRC 2与Dnmt 3甲基转移酶物理相互作用，并阻止它们在IG-DMR处的募集和随后的DNAme，从而允许母体Gtl 2-Rian-Mirg基因座的适当表达。我们的观察提供了一种新的机制，PRC 2抵消了Dnmt 3甲基转移酶在完全多能性所需的印迹位点的作用。
Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with the gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2 the entire locus becomes transcriptionally repressed due to gain of DNA methylation at the intergenic differentially methylated regions (IG-DMR). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Mechanistic study reveals that PRC2 interacts physically with Dnmt3 methyltransferases and prevents their recruitment and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations provide a novel mechanism by which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.