title: Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs.
abstract: Ten-eleven translocation (Tet) family proteins convert 5-methylcytosine to 5-hydroxymethylcytosine. We show that mouse embryonic stem cells (ESCs) depleted of Tet1 and/or Tet2 by RNAi exhibit short telomeres and chromosomal instability, concomitant with reduced telomere recombination. Tet1 and Tet2 double-knockout ESCs also display short telomeres but to a lesser extent. Notably, Tet1/2/3 triple-knockout ESCs show heterogeneous telomere lengths and increased frequency of telomere loss and chromosomal fusion. Mechanistically, Tets depletion or deficiency increases Dnmt3b and decreases 5hmC levels, resulting in elevated methylation levels at sub-telomeres. Consistently, knockdown of Dnmt3b or addition of 2i (MAPK and GSK3β inhibitors), which also inhibits Dnmt3b, reduces telomere shortening, partially rescuing Tet1/2 deficiency. Interestingly, Tet1/2 double or Tet1/2/3 triple knockout in ESCs consistently upregulates Zscan4, which may counteract telomere shortening. Together, Tet enzymes play important roles in telomere maintenance and chromosomal stability of ESCs by modulating sub-telomeric methylation levels.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Renpeng
authors.initials: R
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Jiameng
authors.initials: J
authors.lastname: Dan
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: ShiQing
authors.initials: S
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lingbo
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Junjun
authors.initials: J
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Keefe
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Meelad M
authors.initials: MM
authors.lastname: Dawlaty
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: GuoLiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Chengdu 610041, China. Electronic address: liulin@nankai.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D043171:Chromosomal Instability / Q000235:genetics*; D033481:Chromosomes, Mammalian / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D000097584:DNA Methyltransferase 3B
keywords: DNA methylation; Dnmt3b; Tet; Zscan4; embryonic stem cells; pluripotency; telomere