Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes.
Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes.
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DOI：
10.1186/gb-2013-14-3-r25
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发表时间：
2013-03-25
期刊：
影响因子：
12.3
通讯作者：
Meehan RR
中科院分区：
文献类型：
--
作者：
Reddington JP;Perricone SM;Nestor CE;Reichmann J;Youngson NA;Suzuki M;Reinhardt D;Dunican DS;Prendergast JG;Mjoseng H;Ramsahoye BH;Whitelaw E;Greally JM;Adams IR;Bickmore WA;Meehan RR
DNA甲基化和Polycomb抑制系统是维持转录抑制的重要表观遗传机制。最近的证据表明，DNA甲基化可以减弱Polycomb蛋白组分与染色质的结合，从而在决定其基因组靶向方面发挥作用。然而，DNA甲基化的这种作用在转录调节中是否重要尚不清楚。通过在严重DNA低甲基化的小鼠体细胞中对Polycomb抑制复合物2签名组蛋白标记H3K27me3进行全基因组作图，我们发现低甲基化导致广泛的H3K27me3重新分布，其方式反映了野生型细胞中的局部DNA甲基化状态。出乎意料的是，我们观察到在DNA低甲基化细胞（包括Hox基因簇）中H3K27me3和Polycomb抑制复合物2从Polycomb靶基因启动子的显著损失。重要的是，我们发现许多这些基因在DNA低甲基化的细胞中异位表达，这与Polycomb介导的抑制作用的丧失一致。通过限制Polycomb抑制复合物2靶向，需要完整的DNA甲基化组用于适当的Polycomb介导的基因抑制。这些观察结果确定了DNA甲基化在基因调控中的一个以前未被重视的作用，因此影响了我们对这种表观遗传机制如何促进正常发育和疾病的理解。
DNA methylation and the Polycomb repression system are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear. By genome-wide mapping of the Polycomb Repressive Complex 2-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and Polycomb Repressive Complex 2 from Polycomb target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression. An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining Polycomb Repressive Complex 2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.
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影响因子：
16
作者：
Blackledge NP;Zhou JC;Tolstorukov MY;Farcas AM;Park PJ;Klose RJ
通讯作者：
Klose RJ
影响因子：
7
作者：
Hon, Gary C.;Hawkins, R. David;Ren, Bing
通讯作者：
Ren, Bing
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
21.3
作者：
Hansen, Klaus H.;Bracken, Adrian P.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
30.8
作者：
Broeske, Ann-Marie;Vockentanz, Lena;Rosenbauer, Frank
通讯作者：
Rosenbauer, Frank