@article{7e0201cb52bb4edd87ec3b4119f62b59,
title = "Combined Deficiency of Tet1 and Tet2 Causes Epigenetic Abnormalities but Is Compatible with Postnatal Development",
abstract = "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.",
author = "Dawlaty, {Meelad M.} and Achim Breiling and Thuc Le and G{\"u}nter Raddatz and Barrasa, {M. Inmaculada} and Cheng, {Albert W.} and Qing Gao and Powell, {Benjamin E.} and Zhe Li and Mingjiang Xu and Faull, {Kym F.} and Frank Lyko and Rudolf Jaenisch",
note = "Funding Information: We thank R. Flannery, K. Ganz, D. Fu, and R. Alagappan for help with animal husbandry, histology, and blastocyst injections. We are also grateful to S. Sarkar and Y.C. Hu for help with microscopy, J. Cassady for help with fluorescence-activated cell sorting analysis, J. Kwon and J. Love from the Whitehead Genome Technology Core for help with microarrays, A. Yoon for help with mass spectrometry, and S. Schmidt from the DKFZ Genomics and Proteomics Core Facility for Illumina sequencing services. We thank members of the Jaenisch laboratory for helpful discussions. We are also thankful to Dr. R. Bronson for analyzing histology slides. M.M.D is a Damon Runyon Postdoctoral Fellow. B.E.P is supported by a PhD fellowship from the Boehringer Ingelheim Fonds. A.W.C. is supported by a Croucher scholarship. T.L. is supported by a UCLA Molecular, Cellular and Neurobiology Training Grant, a UCLA Mental Retardation Training Grant, and a Eugene V. Cota-Robles Fellowship. Work in F.L.{\textquoteright}s laboratory was supported by a grant from the Deutsche Forschungsgemeinschaft (SPP 1463). R.J. is funded by NIH grants 5-RO1-HDO45022 and 5-R37-CA084198. ",
year = "2013",
month = feb,
day = "11",
doi = "10.1016/j.devcel.2012.12.015",
language = "English (US)",
volume = "24",
pages = "310--323",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "3",
}