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Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

Jiao Yang1, Renpeng Guo1, Hua Wang1

  • 1State 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.

Cell Reports
|May 18, 2016
PubMed

Insights

Ten-eleven translocation (Tet) enzymes are crucial for maintaining telomere length and chromosomal stability in mouse embryonic stem cells (ESCs). Their depletion leads to telomere shortening and instability by altering sub-telomeric methylation.

Area of Science:

  • Epigenetics
  • Genomics
  • Cell Biology

Background:

  • Ten-eleven translocation (Tet) proteins catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, playing key roles in DNA demethylation.
  • Telomeres, the protective caps of chromosomes, are critical for genomic stability and cellular aging.
  • Embryonic stem cells (ESCs) possess unique self-renewal and differentiation capabilities, making their genomic integrity essential.

Purpose of the Study:

  • To investigate the role of Tet family proteins in telomere maintenance and chromosomal stability in mouse ESCs.
  • To elucidate the molecular mechanisms by which Tet proteins influence telomere integrity.
  • To explore potential therapeutic strategies for mitigating telomere dysfunction in ESCs.

Main Methods:

  • RNA interference (RNAi) was used to deplete Tet1 and Tet2 in mouse ESCs.
  • Telomere length, recombination, loss, and chromosomal fusions were analyzed in Tet-deficient ESCs.
  • DNA methylation levels at sub-telomeric regions and the expression of DNA methyltransferase 3B (Dnmt3b) were assessed.
  • The effect of Dnmt3b inhibition and 2i treatment on telomere shortening was evaluated.

Main Results:

  • Depletion of Tet1 and/or Tet2 in ESCs resulted in shortened telomeres and chromosomal instability, with reduced telomere recombination.
  • Tet1/2/3 triple-knockout ESCs exhibited heterogeneous telomere lengths, increased telomere loss, and chromosomal fusions.
  • Tet deficiency led to increased Dnmt3b levels and decreased 5-hydroxymethylcytosine (5hmC) levels, causing elevated sub-telomeric methylation.
  • Knockdown of Dnmt3b or addition of 2i partially rescued telomere shortening in Tet-deficient ESCs.
  • Upregulation of Zscan4 was observed in Tet-deficient ESCs, potentially counteracting telomere shortening.

Conclusions:

  • Tet enzymes are essential for maintaining telomere length and chromosomal stability in ESCs.
  • Tet proteins regulate telomere integrity by modulating sub-telomeric DNA methylation levels.
  • Targeting Dnmt3b or using specific inhibitors like 2i may offer strategies to address Tet-related telomere dysfunction.
Keywords:
DNA methylationDnmt3bTetZscan4embryonic stem cellspluripotencytelomere

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