Isoform Switch of TET1 Regulates DNA Demethylation and Mouse Development

• DOI: 10.1016/j.molcel.2016.10.030
• Publication Date: 2016-12-01T20:03:01Z
• Authors: Wenhao Zhang; Weikun Xia; Qiujun Wang; Aaron J Towers; Jiayu Chen; Rui Gao; Yu Zhang; Chia-an Yen; Ah Young Lee; Yuanyuan Li; Chen Zhou; Kaili Liu; Jing Zhang; Tian-Peng Gu; Xiuqi Chen; Zai Chang; Danny Leung; Shaorong Gao; Yong-hui Jiang; Wei Xie
• Keywords: Male; 0301 basic medicine; 570; Genomic Imprinting; Mice; 03 medical and health sciences; Isoform switch; Proto-Oncogene Proteins; Animals; Protein Isoforms; Protein Interaction Domains and Motifs; Promoter Regions, Genetic; Ovum; DNA methylation; Binding Sites; Gene Expression Regulation, Developmental; Imprinting; Mouse Embryonic Stem Cells; Embryo, Mammalian; Spermatozoa; Tet1; Chromatin; DNA-Binding Proteins; Epigenetics; CpG Islands; Protein Binding

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.