Loss of Tet Enzymes Compromises Proper Differentiation of Embryonic Stem Cells

被引：245

作者：

Dawlaty, Meelad M. ^{[1
]}

Breiling, Achim ^{[2
]}

Thuc Le ^{[3
,4
,5
,6
,7
]}

Barrasa, M. Inmaculada ^{[1
]}

Raddatz, Guenter ^{[2
]}

Gao, Qing ^{[1
]}

Powell, Benjamin E. ^{[1
]}

Cheng, Albert W. ^{[1
,8
]}

Faull, Kym F. ^{[3
,4
,5
]}

Lyko, Frank ^{[2
]}

Jaenisch, Rudolf ^{[1
,9
]}

机构：

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

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

[3] Univ Calif Los Angeles, David Geffen Sch Med, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, 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] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA

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

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

来源：

DEVELOPMENTAL CELL | 2014年 / 29卷 / 01期

关键词：

DNA METHYLATION; POSTNATAL-DEVELOPMENT; MAMMALIAN DNA; SELF-RENEWAL; 5-HYDROXYMETHYLCYTOSINE; 5-METHYLCYTOSINE; SPECIFICATION; 5-CARBOXYLCYTOSINE; CONVERSION; PROTEINS;

D O I：

10.1016/j.devcel.2014.03.003

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) and are dynamically expressed during development. Whereas loss of individual Tet enzymes or combined deficiency of Tet1/2 allows for embryogenesis, the effect of complete loss of Tet activity and 5hmC marks in development is not established. We have generated Tet1/2/3 triple-knockout (TKO) mouse embryonic stem cells (ESCs) and examined their developmental potential. Combined deficiency of all three Tets depleted 5hmC and impaired ESC differentiation, as seen in poorly differentiated TKO embryoid bodies (EBs) and teratomas. Consistent with impaired differentiation, TKO ESCs contributed poorly to chimeric embryos, a defect rescued by Tet1 reexpression, and could not support embryonic development. Global gene-expression and methylome analyses of TKO EBs revealed promoter hypermethylation and deregulation of genes implicated in embryonic development and differentiation. These findings suggest a requirement for Tet- and 5hmC-mediated DNA demethylation in proper regulation of gene expression during ESC differentiation and development.

引用

页码：102 / 111

页数：10

共 32 条

[1] Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster [J].

Bocker, Michael T. ;

Tuorto, Francesca ;

Raddatz, Guenter ;

Musch, Tanja ;

Yang, Feng-Chun ;

Xu, Mingjiang ;

Lyko, Frank ;

Breiling, Achim .

NATURE COMMUNICATIONS, 2012, 3

[2] Combined Deficiency of Tet1 and Tet2 Causes Epigenetic Abnormalities but Is Compatible with Postnatal Development [J].

Dawlaty, Meelad M. ;

Breiling, Achim ;

Le, Thuc ;

Raddatz, Guenter ;

Barrasa, M. Inmaculada ;

Cheng, Albert W. ;

Gao, Qing ;

Powell, Benjamin E. ;

Li, Zhe ;

Xu, Mingjiang ;

Faull, Kym F. ;

Lyko, Frank ;

Jaenisch, Rudolf .

DEVELOPMENTAL CELL, 2013, 24 (03) :310-323

[3] Tet1 Is Dispensable for Maintaining Pluripotency and Its Loss Is Compatible with Embryonic and Postnatal Development [J].

Dawlaty, Meelad M. ;

Ganz, Kibibi ;

Powell, Benjamin E. ;

Hu, Yueh-Chiang ;

Markoulaki, Styliani ;

Cheng, Albert W. ;

Gao, Qing ;

Kim, Jongpil ;

Choi, Sang-Woon ;

Page, David C. ;

Jaenisch, Rudolf .

CELL STEM CELL, 2011, 9 (02) :166-175

[4] Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells [J].

Gifford, Casey A. ;

Ziller, Michael J. ;

Gu, Hongcang ;

Trapnell, Cole ;

Donaghey, Julie ;

Tsankov, Alexander ;

Shalek, Alex K. ;

Kelley, David R. ;

Shishkin, Alexander A. ;

Issner, Robbyn ;

Zhang, Xiaolan ;

Coyne, Michael ;

Fostel, Jennifer L. ;

Holmes, Laurie ;

Meldrim, Jim ;

Guttman, Mitchell ;

Epstein, Charles ;

Park, Hongkun ;

Kohlbacher, Oliver ;

Rinn, John ;

Gnirke, Andreas ;

Lander, Eric S. ;

Bernstein, Bradley E. ;

Meissner, Alexander .

CELL, 2013, 153 (05) :1149-1163

[5] Aging and Chronic Sun Exposure Cause Distinct Epigenetic Changes in Human Skin [J].

Groenniger, Elke ;

Weber, Barbara ;

Heil, Oliver ;

Peters, Nils ;

Staeb, Franz ;

Wenck, Horst ;

Korn, Bernhard ;

Winnefeld, Marc ;

Lyko, Frank .

PLOS GENETICS, 2010, 6 (05) :6

[6] The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes [J].

Gu, Tian-Peng ;

Guo, Fan ;

Yang, Hui ;

Wu, Hai-Ping ;

Xu, Gui-Fang ;

Liu, Wei ;

Xie, Zhi-Guo ;

Shi, Linyu ;

He, Xinyi ;

Jin, Seung-gi ;

Iqbal, Khursheed ;

Shi, Yujiang Geno ;

Deng, Zixin ;

Szabo, Piroska E. ;

Pfeifer, Gerd P. ;

Li, Jinsong ;

Xu, Guo-Liang .

NATURE, 2011, 477 (7366) :606-U136

[7] Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State Pluripotency [J].

Hackett, Jamie A. ;

Dietmann, Sabine ;

Murakami, Kazuhiro ;

Down, Thomas A. ;

Leitch, Harry G. ;

Surani, M. Azim .

STEM CELL REPORTS, 2013, 1 (06) :518-531

[8] Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway [J].

Hajkova, Petra ;

Jeffries, Sean J. ;

Lee, Caroline ;

Miller, Nigel ;

Jackson, Stephen P. ;

Surani, M. Azim .

SCIENCE, 2010, 329 (5987) :78-82

[9] Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA [J].

He, Yu-Fei ;

Li, Bin-Zhong ;

Li, Zheng ;

Liu, Peng ;

Wang, Yang ;

Tang, Qingyu ;

Ding, Jianping ;

Jia, Yingying ;

Chen, Zhangcheng ;

Li, Lin ;

Sun, Yan ;

Li, Xiuxue ;

Dai, Qing ;

Song, Chun-Xiao ;

Zhang, Kangling ;

He, Chuan ;

Xu, Guo-Liang .

SCIENCE, 2011, 333 (6047) :1303-1307

[10] Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells [J].

Huang, Yun ;

Chavez, Lukas ;

Chang, Xing ;

Wang, Xue ;

Pastor, William A. ;

Kang, Jinsuk ;

Zepeda-Martinez, Jorge A. ;

Pape, Utz J. ;

Jacobsen, Steven E. ;

Peters, Bjoern ;

Rao, Anjana .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (04) :1361-1366

← 1 2 3 4 →