title: Isoform Switch of TET1 Regulates DNA Demethylation and Mouse Development.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Weikun
authors.initials: W
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Towers
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 20092, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Chia-An
authors.initials: CA
authors.lastname: Yen
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Kaili
authors.initials: K
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Tian-Peng
authors.initials: TP
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Xiuqi
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Danny
authors.initials: D
authors.lastname: Leung
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai 20092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: 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. Electronic address: xiewei121@tsinghua.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D001665:Binding Sites; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010063:Ovum / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse
keywords: DNA methylation; Tet1; epigenetics; imprinting; isoform switch