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.

中文翻译：

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TET1在胚胎植入后胚胎中的谱系特异性功能

哺乳动物的TET酶催化DNA脱甲基。尽管已经对它们作为主要的表观遗传调控因子进行了深入研究，但对它们的生理作用以及胚胎植入后功能冗余的程度知之甚少。在这里，我们定义了TET1在小鼠胚胎植入后早期阶段的非冗余角色，即它的旁系同源物Tet2和Tet3。无法检测到表达。TET1调节许多基因，这些基因定义了上皮细胞和胚外外胚层中的分化程序。在上皮细胞中，TET1通过羟甲基化使基因启动子去甲基化，并保持端粒的稳定性。出人意料的是，TET1部分地通过调节编码转录阻遏物JMJD8的基因来独立于甲基化变化而抑制大多数上皮细胞靶基因。在没有TET1的情况下，基因表达失调会导致胚胎缺陷，这些缺陷在近交系中部分渗透，但在非近交小鼠中则完全致命。总体而言，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，这对于正常发育至关重要。