Loss of Tet enzymes compromises proper differentiation of embryonic stem cells.
Loss of Tet enzymes compromises proper differentiation of embryonic stem cells.
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DOI：
10.1016/j.devcel.2014.03.003
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发表时间：
2014-04-14
影响因子：
11.8
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
--
作者：
Dawlaty, Meelad M.;Breiling, Achim;Thuc Le;Barrasa, M. Inmaculada;Raddatz, Guenter;Gao, Qing;Powell, Benjamin E.;Cheng, Albert W.;Faull, Kym F.;Lyko, Frank;Jaenisch, Rudolf
Tet 酶 (Tet1/2/3) 将 5-甲基胞嘧啶 (5mC) 转化为 5-羟基甲基胞嘧啶 (5hmC)，并在发育过程中动态表达。虽然单个 Tet 酶的丧失或 Tet1/2 的联合缺陷允许胚胎发生，但在发育过程中完全丧失 Tet 活性和 5hmC 标记的影响尚未确定。我们生成了 Tet1/2/3 三重敲除 (TKO) 小鼠胚胎干细胞 (ESC) 并检查了它们的发育潜力。所有三种 Tets 的联合缺陷会耗尽 5hmC，并损害 ESC 分化，如低分化 TKO 胚状体 (EB) 和畸胎瘤中所见。与受损的分化一致，TKO-ESC 对嵌合胚胎的贡献很小，这一缺陷通过 Tet1 重新表达得以挽救，并且不能支持胚胎发育。 TKO-EB 的全局基因表达和甲基化组分析揭示了与胚胎发育和分化有关的启动子高甲基化和基因失调。这些发现表明，ESC 分化和发育过程中基因表达的正确调节需要 Tet 和 5hmC 介导的 DNA 去甲基化。
Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and are dynamically expressed during development. While loss of individual Tet enzymes or combined deficiency of Tet1/2 allows for embryogenesis, the effect of complete loss of Tet activity and 5hmC marks in development is not established. We have generated Tet1/2/3 triple knockout (TKO) mouse embryonic stem cells (ESCs) and examined their developmental potential. Combined deficiency of all three Tets depleted 5hmC and impaired ESC differentiation as seen in poorly differentiated TKO embryoid bodies (EBs) and teratomas. Consistent with impaired differentiation, TKO-ESCs contributed poorly to chimeric embryos, a defect rescued by Tet1 re-expression, and could not support embryonic development. Global gene expression and methylome analyses of TKO-EBs revealed promoter hypermethylation and deregulation of genes implicated in embryonic development and differentiation. These findings suggest a requirement for Tet- and 5hmC-mediated DNA demethylation in proper regulation of gene expression during ESC differentiation and development.
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影响因子：
4.5
作者：
Grönniger E;Weber B;Heil O;Peters N;Stäb F;Wenck H;Korn B;Winnefeld M;Lyko F
通讯作者：
Lyko F
影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
64.5
作者：
Gifford CA;Ziller MJ;Gu H;Trapnell C;Donaghey J;Tsankov A;Shalek AK;Kelley DR;Shishkin AA;Issner R;Zhang X;Coyne M;Fostel JL;Holmes L;Meldrim J;Guttman M;Epstein C;Park H;Kohlbacher O;Rinn J;Gnirke A;Lander ES;Bernstein BE;Meissner A
通讯作者：
Meissner A
影响因子：
11.8
作者：
Dawlaty, Meelad M.;Breiling, Achim;Le, Thuc;Raddatz, Guenter;Barrasa, M. Inmaculada;Cheng, Albert W.;Gao, Qing;Powell, Benjamin E.;Li, Zhe;Xu, Mingjiang;Faull, Kym F.;Lyko, Frank;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
64.5
作者：
Okano, M;Bell, DW;Li, E
通讯作者：
Li, E