Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

Jiao Yang, Renpeng Guo, Hua Wang, Xiaoying Ye, Zhongcheng Zhou, Jiameng Dan, Haiying Wang, Peng Gong, Wei Deng, Yu Yin, Shi Qing Mao, Lingbo Wang, Junjun Ding, Jinsong Li, David L. Keefe, Meelad M. Dawlaty, Jianlong Wang, Guo Liang Xu, Lin Liu

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1809-1821
Number of pages13
JournalCell Reports
Volume15
Issue number8
DOIs
StatePublished - May 24 2016

Fingerprint

Chromosomal Instability
Telomere
Stem cells
Maintenance
Embryonic Stem Cells
Enzymes
Methylation
Telomere Shortening
5-Methylcytosine
Fusion reactions
Protein Transport
RNA Interference
Mouse Embryonic Stem Cells
Genetic Recombination
Up-Regulation
Proteins

Keywords

  • DNA methylation
  • Dnmt3b
  • Embryonic stem cells
  • Pluripotency
  • Telomere
  • Tet
  • Zscan4

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, J., Guo, R., Wang, H., Ye, X., Zhou, Z., Dan, J., ... Liu, L. (2016). Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs. Cell Reports, 15(8), 1809-1821. https://doi.org/10.1016/j.celrep.2016.04.058

Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs. / Yang, Jiao; Guo, Renpeng; Wang, Hua; Ye, Xiaoying; Zhou, Zhongcheng; Dan, Jiameng; Wang, Haiying; Gong, Peng; Deng, Wei; Yin, Yu; Mao, Shi Qing; Wang, Lingbo; Ding, Junjun; Li, Jinsong; Keefe, David L.; Dawlaty, Meelad M.; Wang, Jianlong; Xu, Guo Liang; Liu, Lin.

In: Cell Reports, Vol. 15, No. 8, 24.05.2016, p. 1809-1821.

Research output: Contribution to journalArticle

Yang, J, Guo, R, Wang, H, Ye, X, Zhou, Z, Dan, J, Wang, H, Gong, P, Deng, W, Yin, Y, Mao, SQ, Wang, L, Ding, J, Li, J, Keefe, DL, Dawlaty, MM, Wang, J, Xu, GL & Liu, L 2016, 'Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs', Cell Reports, vol. 15, no. 8, pp. 1809-1821. https://doi.org/10.1016/j.celrep.2016.04.058
Yang, Jiao ; Guo, Renpeng ; Wang, Hua ; Ye, Xiaoying ; Zhou, Zhongcheng ; Dan, Jiameng ; Wang, Haiying ; Gong, Peng ; Deng, Wei ; Yin, Yu ; Mao, Shi Qing ; Wang, Lingbo ; Ding, Junjun ; Li, Jinsong ; Keefe, David L. ; Dawlaty, Meelad M. ; Wang, Jianlong ; Xu, Guo Liang ; Liu, Lin. / Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs. In: Cell Reports. 2016 ; Vol. 15, No. 8. pp. 1809-1821.
@article{77d02780c0224cf3a927097c4a67cca3,
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.",
keywords = "DNA methylation, Dnmt3b, Embryonic stem cells, Pluripotency, Telomere, Tet, Zscan4",
author = "Jiao Yang and Renpeng Guo and Hua Wang and Xiaoying Ye and Zhongcheng Zhou and Jiameng Dan and Haiying Wang and Peng Gong and Wei Deng and Yu Yin and Mao, {Shi Qing} and Lingbo Wang and Junjun Ding and Jinsong Li and Keefe, {David L.} and Dawlaty, {Meelad M.} and Jianlong Wang and Xu, {Guo Liang} and Lin Liu",
year = "2016",
month = "5",
day = "24",
doi = "10.1016/j.celrep.2016.04.058",
language = "English (US)",
volume = "15",
pages = "1809--1821",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",

}

TY - JOUR

T1 - Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

AU - Yang, Jiao

AU - Guo, Renpeng

AU - Wang, Hua

AU - Ye, Xiaoying

AU - Zhou, Zhongcheng

AU - Dan, Jiameng

AU - Wang, Haiying

AU - Gong, Peng

AU - Deng, Wei

AU - Yin, Yu

AU - Mao, Shi Qing

AU - Wang, Lingbo

AU - Ding, Junjun

AU - Li, Jinsong

AU - Keefe, David L.

AU - Dawlaty, Meelad M.

AU - Wang, Jianlong

AU - Xu, Guo Liang

AU - Liu, Lin

PY - 2016/5/24

Y1 - 2016/5/24

N2 - 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.

AB - 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.

KW - DNA methylation

KW - Dnmt3b

KW - Embryonic stem cells

KW - Pluripotency

KW - Telomere

KW - Tet

KW - Zscan4

UR - http://www.scopus.com/inward/record.url?scp=84966602687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966602687&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.04.058

DO - 10.1016/j.celrep.2016.04.058

M3 - Article

VL - 15

SP - 1809

EP - 1821

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

ER -