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Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development

Meelad M Dawlaty1, Achim Breiling, Thuc Le

  • 1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

Developmental Cell
|January 29, 2013
PubMed

Insights

Tet enzymes (Tet1/2/3) are crucial for converting 5-methylcytosine to 5-hydroxymethylcytosine. Tet1 and Tet2 double-knockout mice show developmental defects and imprinting errors, indicating overlapping roles.

Area of Science:

  • Epigenetics and Gene Regulation
  • Developmental Biology
  • Mammalian Genetics

Background:

  • Tet enzymes (Tet1, Tet2, Tet3) catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).
  • Individual Tet1 or Tet2 knockout mice are viable, suggesting potential functional redundancy between these enzymes during development.

Purpose of the Study:

  • To investigate the overlapping roles of Tet1 and Tet2 in embryonic development and cellular pluripotency.
  • To characterize the epigenetic consequences of combined Tet1 and Tet2 deficiency.

Main Methods:

  • Generation of Tet1 and Tet2 double-knockout (DKO) embryonic stem cells (ESCs) and mice.
  • Analysis of 5hmC and 5mC levels in DKO ESCs and tissues.
  • Assessment of developmental phenotypes in chimeric embryos and DKO mice.
  • Evaluation of methylation patterns at imprinted loci.

Main Results:

  • DKO ESCs maintained pluripotency but showed depletion of 5hmC and caused developmental defects in chimeras.
  • DKO mice exhibited reduced 5hmC, increased 5mC, and abnormal methylation at imprinted loci.
  • While some DKO embryos had midgestation defects and perinatal lethality, viable and seemingly normal mice were obtained.
  • Fertility was reduced in DKO mice, particularly in females, with smaller ovaries.

Conclusions:

  • Loss of both Tet1 and Tet2 is compatible with mammalian development but leads to significant epigenetic dysregulation, including hypermethylation and compromised imprinting.
  • The results suggest a substantial contribution of Tet3 to 5mC hydroxylation during development, compensating for the loss of Tet1 and Tet2.
  • Tet1 and Tet2 possess overlapping functions critical for maintaining epigenetic homeostasis and normal development.

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