Maintenance of self‐renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b

Genes to Cells - Tập 11 Số 7 - Trang 805-814 - 2006
Akiko Tsumura1,2, Tomohiro Hayakawa3, Yuichi Kumaki4,5, Shin‐ichiro Takebayashi2, Masaki Sakaue2, Chisa Matsuoka2, Kunitada Shimotohno1, Fuyuki Ishikawa6, En Li7, Hiroki R. Ueda5, Jun‐ichi Nakayama3, Masaki Okano2
1Department of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8501, Japan
2Laboratory for Mammalian Epigenetic Studies,
3Laboratory for Chromatin Dynamics, and
4INTEC Web and Genome Informatics Corp., 1-3-3 Shinsuna, Koto-ku, Tokyo 136-8637, Japan
5Laboratory for Systems Biology, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
6Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan
7Epigenetics Program, Novartis Institute for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA

Tóm tắt

DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b cooperatively regulate cytosine methylation in CpG dinucleotides in mammalian genomes, providing an epigenetic basis for gene silencing and maintenance of genome integrity. Proper CpG methylation is required for the normal growth of various somatic cell types, indicating its essential role in the basic cellular function of mammalian cells. Previous studies using Dnmt1−/– or Dnmt3a−/–Dnmt3b−/– ES cells, however, have shown that undifferentiated embryonic stem (ES) cells can tolerate hypomethylation for their proliferation. In an attempt to investigate the effects of the complete loss of CpG DNA methyltransferase function, we established mouse ES cells lacking all three of these enzymes by gene targeting. Despite the absence of CpG methylation, as demonstrated by genome‐wide methylation analysis, these triple knockout (TKO) ES cells grew robustly and maintained their undifferentiated characteristics. TKO ES cells retained pericentromeric heterochromatin domains marked with methylation at Lys9 of histone H3 and heterochromatin protein‐1, and maintained their normal chromosome numbers. Our results indicate that ES cells can maintain stem cell properties and chromosomal stability in the absence of CpG methylation and CpG DNA methyltransferases.

Từ khóa


Tài liệu tham khảo

10.1016/S1535-6108(02)00234-9

10.1101/gad.947102

10.1038/nature02886

10.1128/MCB.23.16.5594-5605.2003

10.1093/nar/22.15.2990

10.1074/jbc.M413246200

10.1126/science.1083557

10.1038/nrg1748

10.1128/MCB.19.9.6415

10.1074/jbc.M302283200

10.1126/science.1083558

10.1016/S0925-4773(02)00181-8

10.1002/mrd.20387

10.1073/pnas.0401346101

10.1128/MCB.24.20.8862-8871.2004

10.1038/nature731

10.1038/83730

10.1093/embo-reports/kve022

10.1038/nrg816

10.1038/561

10.1128/MCB.24.13.5710-5720.2004

10.1016/S0960-9822(03)00432-9

10.1242/dev.122.10.3195

10.1038/nrg887

10.1016/0092-8674(92)90611-F

10.1242/jcs.02291

10.1038/nrm1355

10.1016/j.devcel.2005.10.017

10.1038/30764

10.1038/12659

10.1016/S0092-8674(00)81656-6

10.1073/pnas.97.10.5237

10.1038/416552a

10.1038/nrg1655

10.1016/j.molcel.2004.06.043

10.1038/35104508

10.1073/pnas.1432939100

10.1038/nature04431

10.1038/12664

10.1038/2413

10.1038/46052

10.1093/emboj/cdg493

10.1101/gad.13.15.1924

Thông tin
Thông tin xuất bản

Genes to Cells

Tập 11 Số 7

805-814

Thông tin tác giả