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Distinct Roles of DMAP1 in Mouse Development

机译：DMAP1在小鼠发育中的不同作用

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DMAP1 (DNMT1-associated protein 1) is a member of the TIP60-p400 complex that maintains embryonic stem (ES) cell pluripotency and a complex containing the somatic form of DNA methyltransferase 1 (DNMT1s). DMAP1 interacts with DNMT1s through a domain that is absent in Dnmt1V/V mice expressing just the oocyte form (DNMT1o). A Dmap1-null allele was generated to study the role of DMAP1 in development. Consistent with the phenotypes of loss of other members of the TIP60-p400 complex, Dmap1?/? mice died during preimplantation in both Dnmt1+/+ and Dnmt1V/V backgrounds. Unexpectedly, in the Dnmt1V/V background, Dmap1+/? parents produced mainly Dmap1+/? mice. Most Dmap1+/+ progeny died during midgestation, with loss of DNA methylation on imprinted genes, suggesting that DMAP1 influences maintenance methylation mediated by DNMT1o. In this regard, a DMAP1-DNMT1o complex was detected in ES cells when DNMT1o was stably expressed but not when transiently expressed, indicating a novel interaction between DMAP1 and DNMT1o. These results suggest that DMAP1-DNMT1s and DMAP1-DNMT1o interactions are essential for normal development and that DMAP1-DNMT1o complexes are not readily formed in the embryo. Therefore, DMAP1 mediates distinct preimplantation epigenetic reprogramming processes: TIP60-p400 nucleosome remodeling and DNMT1 maintenance methylation.
机译：DMAP1（与DNMT1相关的蛋白质1）是TIP60-p400复合物的成员，该复合物可维持胚胎干（ES）细胞多能性，并且是一种包含体细胞形式的DNA甲基转移酶1（DNMT1s）的复合物。 DMAP1通过 Dnmt1 V / V 中不存在的域与DNMT1交互。只表达卵母细胞形式（DNMT10）的小鼠。产生了一个 Dmap1 -无效等位基因，以研究DMAP1在发育中的作用。与TIP60-p400复合体其他成员的丢失表型一致， Dmap1 ？/？小鼠在植入前均在两个 Dnmt1 + / + 和 Dnmt1 V / V 背景。出乎意料的是，在 Dnmt1 V / V 背景中， Dmap1 < / em> + /？父母主要生产 Dmap1 + /？小鼠。大多数 Dmap1 + / + 后代在妊娠中期死亡，印迹基因的DNA甲基化丢失，表明DMAP1影响DNMT10o介导的维持甲基化。在这方面，当稳定表达DNMT10而不是瞬时表达时，在ES细胞中检测到DMAP1-DNMT10o复合物，这表明DMAP1和DNMT1o之间存在新的相互作用。这些结果表明，DMAP1-DNMT1s和DMAP1-DNMT1o相互作用对于正常发育必不可少，并且DMAP1-DNMT10o复合物不容易在胚胎中形成。因此，DMAP1介导不同的植入前表观遗传重编程过程：TIP60-p400核小体重塑和DNMT1维持甲基化。

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