Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA.
Mol Cell Biol. 2011 May;31(9):1861-9. doi: 10.1128/MCB.01390-10. Epub 2011 Mar 7.
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 Dnmt1(V)(/)(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 Dnmt1(V)(/)(V) backgrounds. Unexpectedly, in the Dnmt1(V)(/)(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.
DMAP1（DNMT1 相关蛋白 1）是 TIP60-p400 复合物的成员，该复合物维持胚胎干细胞（ES）细胞的多能性，并且包含体细胞形式的 DNA 甲基转移酶 1（DNMT1s）。DMAP1 通过一个与 Dnmt1(V)(/)(V) 小鼠中仅表达卵母细胞形式（DNMT1o）的 DNMT1s 相互作用的结构域与 DNMT1s 相互作用。生成 Dmap1 缺失等位基因以研究 DMAP1 在发育中的作用。与 TIP60-p400 复合物其他成员缺失的表型一致，Dmap1(-/-) 小鼠在 Dnmt1(+/+) 和 Dnmt1(V)(/)(V) 背景下的着床前死亡。出乎意料的是，在 Dnmt1(V)(/)(V) 背景下，Dmap1(+/-) 父母主要产生 Dmap1(+/-) 小鼠。大多数 Dmap1(+/+) 后代在中期妊娠期间死亡，印记基因的 DNA 甲基化丢失，表明 DMAP1 影响由 DNMT1o 介导的维持甲基化。在这种情况下，当稳定表达 DNMT1o 但不是瞬时表达时，在 ES 细胞中检测到 DMAP1-DNMT1o 复合物，表明 DMAP1 与 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至关重要，并且 DMAP1-DNMT1o 复合物在胚胎中不易形成。因此，DMAP1 介导不同的着床前表观遗传重编程过程：TIP60-p400 核小体重塑和 DNMT1 维持甲基化。
