Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA.
Mol Cell. 2016 Dec 15;64(6):1062-1073. doi: 10.1016/j.molcel.2016.10.030. Epub 2016 Dec 1.
The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. However, it remains elusive how exactly they target substrates and execute oxidation. Interestingly, we found that, in mice, the full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (ESCs), and primordial germ cells (PGCs). By contrast, a short isoform (TET1s) is preferentially expressed in somatic cells, which lacks the N terminus including the CXXC domain, a DNA-binding module that often recognizes CpG islands (CGIs) where TET1 predominantly occupies. Unexpectedly, TET1s can still bind CGIs despite the fact that its global chromatin binding is significantly reduced. Interestingly, global chromatin binding, but not targeted binding at CGIs, is correlated with TET1-mediated demethylation. Finally, mice with exclusive expression of Tet1s failed to erase imprints in PGCs and displayed developmental defects in progeny. These data show that isoform switch of TET1 regulates epigenetic memory erasure and mouse development.
甲基胞嘧啶氧化酶 TET 蛋白在 DNA 去甲基化和发育中发挥重要作用。然而，它们如何准确地靶向底物并执行氧化仍然难以捉摸。有趣的是，我们发现，在小鼠中，全长 TET1 异构体（TET1e）仅限于早期胚胎、胚胎干细胞（ESCs）和原始生殖细胞（PGCs）。相比之下，短异构体（TET1s）在体细胞中优先表达，它缺乏包括CXXC 结构域在内的 N 端，CXXC 结构域是一个 DNA 结合模块，通常识别 TET1 主要占据的 CpG 岛（CGIs）。出乎意料的是，尽管 TET1s 的全局染色质结合显著减少，但它仍然可以结合 CGIs。有趣的是，全局染色质结合，而不是靶向 CGIs 的结合，与 TET1 介导的去甲基化相关。最后，仅表达 Tet1s 的小鼠未能在 PGCs 中消除印迹，并在后代中表现出发育缺陷。这些数据表明 TET1 的异构体转换调节表观遗传记忆擦除和小鼠发育。
