TY - JOUR
T1 - Role of tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification
AU - Ito, Shinsuke
AU - Dalessio, Ana C.
AU - Taranova, Olena V.
AU - Hong, Kwonho
AU - Sowers, Lawrence C.
AU - Zhang, Yi
N1 - Funding Information:
Acknowledgements We thank M. Okano for the J1 and DNMT triple knockout ES cells; J. He and A. Nguyen for help in FACS sorting; and S. Wu for critical reading of the manuscript. This work was supported by NIH grants GM68804 (to Y.Z.) and CA084487 (to L.C.S.). S.I. is a research fellow of the Japan Society for the Promotion of Science. O.T. is a postdoctoral fellow of Juvenile Diabetes Research Foundation International. Y.Z. is an Investigator of the Howard Hughes Medical Institute.
PY - 2010/8/26
Y1 - 2010/8/26
N2 - DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.
AB - DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.
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U2 - 10.1038/nature09303
DO - 10.1038/nature09303
M3 - Article
C2 - 20639862
SN - 0028-0836
VL - 466
SP - 1129
EP - 1133
JO - Nature
JF - Nature
IS - 7310
ER -