Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 2011 Feb 04;8(2):200-13
Date
02/08/2011Pubmed ID
21295276Pubmed Central ID
PMC3134318DOI
10.1016/j.stem.2011.01.008Scopus ID
2-s2.0-79551587102 (requires institutional sign-in at Scopus site) 652 CitationsAbstract
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.
Author List
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 AAuthor
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
5-MethylcytosineAnimals
Binding Sites
Cell Differentiation
Cell Lineage
Chromatin Immunoprecipitation
Computational Biology
Cytosine
DNA-Binding Proteins
Dioxygenases
Embryonic Stem Cells
Mice
Octamer Transcription Factor-3
Proto-Oncogene Proteins
Teratoma
