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

作者：Meelad M. Dawlaty, Achim Breiling, Thuc M. Le, G. Raddatz, M. I. Barrasa, Albert W. Cheng, Qing Gao, B. E. Powell, Zhe Li, Mingjiang Xu, K. F. Faull, F. Lyko, R. Jaenisch · 发表于：Developmental Cell · 年份：2013 · DOI：10.1016/j.devcel.2012.12.015 · 被引用次数：448 · 研究领域：Biology、Medicine

Summary 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 whether these enzymes have overlapping roles in development. Here, we have generated Tet1 and Tet2 double knockout (DKO) 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 mid-gestation 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. It also suggests a significant contribution of Tet3 to hydroxylation of 5mC during development.