Combined Deficiency of Tet1 and Tet2 Causes Epigenetic Abnormalities but Is Compatible with Postnatal Development

被引：337

作者：

Dawlaty, Meelad M. ^{[1
]}

Breiling, Achim ^{[2
]}

Le, Thuc ^{[3
,4
,5
]}

Raddatz, Guenter ^{[2
]}

Barrasa, M. Inmaculada ^{[1
]}

Cheng, Albert W. ^{[1
,6
]}

Gao, Qing ^{[1
]}

Powell, Benjamin E. ^{[1
]}

Li, Zhe ^{[8
]}

Xu, Mingjiang ^{[8
]}

Faull, Kym F. ^{[4
,5
]}

Lyko, Frank ^{[2
]}

Jaenisch, Rudolf ^{[1
,7
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] DKFZ ZMBH Alliance, German Canc Res Ctr, Div Epigenet, D-69120 Heidelberg, Germany

[3] Univ Calif Los Angeles, David Geffen Sch Med, Broad Stem Cell Res Ctr, Dept Human Genet, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA

[6] MIT, Computat & Syst Biol Program, Cambridge, MA 02142 USA

[7] MIT, Dept Biol, Cambridge, MA 02142 USA

[8] Indiana Univ, Indiana Univ Sch Med, Melvin & Bren Simon Canc Ctr, Dept Pediat,Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

来源：

DEVELOPMENTAL CELL | 2013年 / 24卷 / 03期

关键词：

EMBRYONIC STEM-CELLS; ACTIVE DNA DEMETHYLATION; MAMMALIAN DNA; SELF-RENEWAL; 5-HYDROXYMETHYLCYTOSINE; MOUSE; GENES; 5-METHYLCYTOSINE; PROTEINS; GENOME;

D O I：

10.1016/j.devcel.2012.12.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：310 / 323

页数：14

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