Lineage-specific functions of TET1 in the postimplantation mouse embryo.
Lineage-specific functions of TET1 in the postimplantation mouse embryo.
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DOI：
10.1038/ng.3868
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发表时间：
2017-07
期刊：
影响因子：
30.8
通讯作者：
Koh KP
中科院分区：
文献类型：
--
作者：
Khoueiry R;Sohni A;Thienpont B;Luo X;Velde JV;Bartoccetti M;Boeckx B;Zwijsen A;Rao A;Lambrechts D;Koh KP
哺乳动物的TET酶催化DNA去甲基化。虽然它们作为主要的表观遗传调节因子已被广泛研究，但人们对它们的生理作用和胚胎着床后功能冗余的程度知之甚少。在这里，我们定义了TET1在小鼠胚胎的早期植入后阶段的非冗余作用，当它的类似物Tet2和Tet3没有被检测到表达时。TET1调控许多决定外胚层和胚外胚层分化程序的基因。在外胚层细胞中，TET1通过羟甲基化使基因启动子去甲基化并维持端粒稳定性。令人惊讶的是，TET1独立于甲基化变化抑制大多数外胚层靶基因，部分通过调控编码转录抑制因子JMJD8的基因。在缺乏TET1的情况下，基因表达失调会导致胚胎缺陷，这在近交系中是部分渗透的，但在非近交系小鼠中是完全致命的。总的来说，我们的研究强调了TET1的催化和非催化活性之间的相互作用，这对正常发育至关重要。
The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm. In epiblast cells, TET1 demethylates gene promoters via hydroxymethylation and maintains telomere stability. Surprisingly, TET1 represses a majority of epiblast target genes independently of methylation changes, in part through regulation of the gene encoding the transcriptional repressor JMJD8. Dysregulated gene expression in the absence of TET1 causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice. Collectively, our study highlights an interplay between the catalytic and non-catalytic activities of TET1 that is essential for normal development.
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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
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Jaenisch, Rudolf
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影响因子：
11.8
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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：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I