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PMID: 21295276 Published · ppublish English Journal Article Research Support, American Recovery and Reinvestment Act Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells.

Cell stem cell ·Vol. 8 ·No. 2 ·2011-02-04 ·Pages 200-13

Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A

Abstract

TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs.

MeSH Terms
5-Methylcytosine/analogs & derivatives Animals Binding Sites/genetics,physiology Cell Differentiation/genetics,physiology Cell Lineage Chromatin Immunoprecipitation Computational Biology Cytosine/analogs & derivatives,metabolism DNA-Binding Proteins/genetics,metabolism Dioxygenases Embryonic Stem Cells/cytology,metabolism Mice Octamer Transcription Factor-3/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Teratoma/genetics,metabolism
Chemicals
DNA-Binding Proteins Octamer Transcription Factor-3 Pou5f1 protein, mouse Proto-Oncogene Proteins TET1 protein, mouse 5-hydroxymethylcytosine 5-Methylcytosine Cytosine Dioxygenases Tet2 protein, mouse
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Koh Kian Peng
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
Yabuuchi Akiko
Rao Sridhar
Huang Yun
Cunniff Kerrianne
Nardone Julie
Laiho Asta
Tahiliani Mamta
Sommer Cesar A
Mostoslavsky Gustavo
Lahesmaa Riitta
Orkin Stuart H
Rodig Scott J
Daley George Q
Rao Anjana
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2011.01.008
Published
2011-02-04
Pages
200-13
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC3134318
Subset
IM
Grants
NIDDK NIH HHS · R01 DK070055-03 · United States
NIDDK NIH HHS · R01-DK70055 · United States
NHLBI NIH HHS · RC2-HL102815 · United States
NIAID NIH HHS · R01 AI044432 · United States
Howard Hughes Medical Institute · United States
NIAID NIH HHS · R01 AI044432-10 · United States
NHLBI NIH HHS · UO1-HL100001 · United States
NCI NIH HHS · CA42471 · United States
NCI NIH HHS · R01 CA042471-24 · United States
NCI NIH HHS · R37 CA042471 · United States
NIAID NIH HHS · R01 AI044432-12 · United States
NIAID NIH HHS · R01 AI044432-11 · United States
NCI NIH HHS · R01 CA042471-23 · United States
NIDDK NIH HHS · R01 DK059279 · United States
NICHD NIH HHS · R01 HD065812 · United States
NIDDK NIH HHS · R01 DK070055 · United States
NHLBI NIH HHS · U01 HL100001-01 · United States
NHLBI NIH HHS · U01 HL100001 · United States
NHLBI NIH HHS · RC2 HL102815 · United States
NIDDK NIH HHS · R01 DK059279-08 · United States
NCI NIH HHS · R01 CA042471-22A1 · United States
NIDA NIH HHS · RC1 DA028422-01 · United States
NCI NIH HHS · R01 CA042471 · United States
NIAID NIH HHS · AI44432 · United States
NIDA NIH HHS · RC1 DA028422 · United States
NIDA NIH HHS · RC1 DA028422-02 · United States
NHLBI NIH HHS · RC2 HL102815-01 · United States
NIDDK NIH HHS · R01-DK59279 · United States
Databases
GEO
GSE26900
Corrections
CommentIn
PMID: 21295264
External Links
PubMed source DOI: 10.1016/j.stem.2011.01.008 PMC Full Text View journal details
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