Tet1 and Tet2 Regulate 5-Hydroxymethylcytosine Production and Cell Lineage Specification in Mouse Embryonic Stem Cells

被引:619
作者
Koh, Kian Peng [1 ,12 ]
Yabuuchi, Akiko [2 ,3 ]
Rao, Sridhar [2 ,3 ]
Huang, Yun [1 ,12 ]
Cunniff, Kerrianne [2 ,3 ]
Nardone, Julie [4 ]
Laiho, Asta [5 ,6 ]
Tahiliani, Mamta [1 ,12 ]
Sommer, Cesar A. [7 ,8 ]
Mostoslavsky, Gustavo [7 ,8 ]
Lahesmaa, Riitta [1 ,5 ,6 ,12 ]
Orkin, Stuart H. [2 ,3 ,9 ]
Rodig, Scott J. [10 ]
Daley, George Q. [2 ,3 ,9 ,11 ]
Rao, Anjana [1 ,12 ]
机构
[1] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
[2] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA
[3] Harvard Stem Cell Inst, Dana Faber Canc Inst, Boston, MA 02115 USA
[4] Cell Signaling Technol, Bioinformat, Danvers, MA 01923 USA
[5] Univ Turku, Turku Ctr Biotechnol, FI-20520 Turku, Finland
[6] Abo Akad Univ, FI-20520 Turku, Finland
[7] Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA
[8] Boston Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02118 USA
[9] Howard Hughes Med Inst, Boston, MA 02115 USA
[10] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[11] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[12] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA
基金
芬兰科学院;
关键词
DNA METHYLATION; SELF-RENEWAL; TRANSCRIPTIONAL NETWORK; MYELOID CANCERS; GENOMIC DNA; 5-METHYLCYTOSINE; PLURIPOTENCY; CONVERSION; PROTEINS; ROLES;
D O I
10.1016/j.stem.2011.01.008
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:200 / 213
页数:14
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