Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development.
Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in various embryonic and adult tissues. Mice mutant for either Tet1 or Tet2 are viable, raising the question of whether these enzymes have overlapping roles in development. Here we have generated Tet1 and Tet2 double-knockout (DKO) embryonic stem cells (ESCs) and mice. DKO ESCs remained pluripotent but were depleted of 5hmC and caused developmental defects in chimeric embryos. While a fraction of double-mutant embryos exhibited midgestation abnormalities with perinatal lethality, viable and overtly normal Tet1/Tet2-deficient mice were also obtained. DKO mice had reduced 5hmC and increased 5mC levels and abnormal methylation at various imprinted loci. Nevertheless, animals of both sexes were fertile, with females having smaller ovaries and reduced fertility. Our data show that loss of both enzymes is compatible with development but promotes hypermethylation and compromises imprinting. The data also suggest a significant contribution of Tet3 to hydroxylation of 5mC during development.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Meelad M
MM
Dawlaty
Achim
A
Breiling
Thuc
T
Le
Günter
G
Raddatz
M Inmaculada
MI
Barrasa
Albert W
AW
Cheng
Qing
Q
Gao
Benjamin E
BE
Powell
Zhe
Z
Li
Mingjiang
M
Xu
Kym F
KF
Faull
Frank
F
Lyko
Rudolf
R
Jaenisch
D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D018392:Genomic Imprinting; D006801:Humans; D006900:Hydroxylation; D008297:Male; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse