A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus.
A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus.
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DOI：
10.1016/j.devcel.2021.10.004
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发表时间：
2021-11-22
影响因子：
11.8
通讯作者：
Apostolou E
中科院分区：
文献类型：
--
作者：
Aronson BE;Scourzic L;Shah V;Swanzey E;Kloetgen A;Polyzos A;Sinha A;Azziz A;Caspi I;Li J;Pelham-Webb B;Glenn RA;Vierbuchen T;Wichterle H;Tsirigos A;Dawlaty MM;Stadtfeld M;Apostolou E
印迹丢失(LOI)会导致严重的发育缺陷，但其预防LOI的机制仍不完全清楚。在这里，我们剖析了多能干细胞中必要的Dlk1-dio3基因座(称为IG-DMR)印记控制区的功能成分。我们证明IG-DMR由两个拮抗元件组成：父系甲基化的CpG岛阻止Tet双加氧酶的招募，以及母系非甲基化的非规范增强子通过对抗从头DNA甲基转移酶来确保Gtl2 lncRNA的表达。这些元素的遗传或表观遗传编辑导致不同的LOI表型，具有等位基因特异性基因表达、DNA甲基化和3D染色质拓扑的特征变化。虽然抑制Gtl2启动子会导致印迹失调，但LOI表型的稳定性取决于IG-DMR，这表明了一个功能层次。这些发现确立了IG-DMR作为一种双向控制元件，通过对DNA(去)甲基化机制的等位基因特异性限制来维持印记。Aronson、SCourzic等人的研究成果。确定确保主要印迹基因Dlk1-dio3的表观遗传稳定性的基因调控元件，Dlk1-dio3编码重要的发育调节因子。它们表明，这些元件通过以等位基因特异性的方式对抗从头DNA甲基化或去甲基化来发挥作用，为表观遗传基因表达控制提供了一个框架。
Loss of imprinting (LOI) results in severe developmental defects, but the mechanisms preventing LOI remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) in pluripotent stem cells. We demonstrate that the IG-DMR consists of two antagonistic elements: a paternally methylated CpG-island that prevents recruitment of TET dioxygenases and a maternally unmethylated non-canonical enhancer that ensures expression of the Gtl2 lncRNA by counteracting de novo DNA methyltransferases. Genetic or epigenetic editing of these elements leads to distinct LOI phenotypes with characteristic alternations of allele-specific gene expression, DNA methylation and 3D chromatin topology. Although repression of the Gtl2 promoter results in dysregulated imprinting, the stability of LOI phenotypes depends on the IG-DMR, suggesting a functional hierarchy. These findings establish the IG-DMR as a bipartite control element that maintains imprinting by allele-specific restriction of the DNA (de)methylation machinery. Aronson, Scourzic et al. identify gene regulatory elements that ensure epigenetic stability at the major imprinted locus, Dlk1-Dio3, encoding essential developmental regulators. They show that these elements operate by counteracting de novo DNA methylation or demethylation in an allele-specific manner, providing a framework for epigenetic gene expression control.
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影响因子：
8.8
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
通讯作者：
Orkin SH
影响因子：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
48
作者：
Danko CG;Hyland SL;Core LJ;Martins AL;Waters CT;Lee HW;Cheung VG;Kraus WL;Lis JT;Siepel A
通讯作者：
Siepel A
影响因子：
4.6
作者：
Hara, Satoshi;Terao, Miho;Takada, Shuji
通讯作者：
Takada, Shuji