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

By Kian Peng Koh, A. Yabuuchi, Sridhar Rao, Yun Huang, K. Cunniff, J. Nardone, Asta Laiho, Mamta Tahiliani, Cesar Sommer, G. Mostoslavsky and 5 more. Cell Stem Cell, 2011

782 citations recorded by the source corpus.

SUMMARY 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 (ES) cells, and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ES cells depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1, and display hyperactive Nodal signalling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ES cells activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in mid-gestation embryo chimeras. Consistent with these findings, Tet1-depleted ES cells form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm and ectopic appearance of trophoblastic giant cells. Thus 5hmC is a novel epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ES cells.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6cd83a4e37295b640fae1c2083583f875eddcda8

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In Molecular Biology

1. Hao Wu
2. Yi Zhang
3. Chuan He
4. Bing Ren
5. Qing Dai
6. Jörn Walter
7. E. Nestler
8. Peng Jin

Citations in the corpus

• 5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging (2011, background): “(c,g) Adult stable DhMRs in cerebellum (6,782) and hippocampus (90), defined as DhMRs identified at both 6 weeks and 1 year relative to P7.”
• TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. (2011, positive): “Tet2 also controls homeostasis of murine hematopoietic stem and progenitor cells, in keeping with the reported role of TET2 in ES cell differentiation (Koh et al., 2011).”
• DNA Demethylation Dynamics (2011, background): “…5hmC and TET in regulating DNA demethylation (Cortellino et al., 2011; Ficz et al., 2011; Guo et al., 2011; He et al., 2011; Ito et al., 2010, 2011; Koh et al., 2011; Kriaucionis and Heintz, 2009; Pastor et al., 2011; Tahiliani et al., 2009; Williams et al., 2011; Wossidlo et al., 2011; Wu et…”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “Single or combined depletion of Tet1 and Tet2 in mouse ESCs, by short-hairpin RNA (shRNA)-mediated knockdown or genetic inactivation, produced variable in vitro phenotypes (Dawlaty et al., 2013; Dawlaty et al., 2011; Ficz et al., 2011; Freudenberg et al., 2012; Ito et al., 2010; Koh et al., 2011; Wi”
• 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. (2011, background): “Recent data already point towards an important regulatory role of Tet1- and Tet2-mediated oxidation for ES cell development and maintenance of pluripotenc”
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “It has been reported that Tet1 can replace the role of Oct4 in inducible pluripotent stem cell (iPSC) reprogramming, a process that is implicated in the regulatory circuit of ESCs [68].”
• Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, positive): “The TET proteins, which are responsible for conversion of 5mC to 5hmC, have been shown to function in ESC regulation, myelopoiesis and zygote development (Dawlaty et al., 2011; Gu et al., 2011; Iqbal et al., 2011; Ito et al., 2010; Ko et al., 2010; Koh et al., 2011; Wossidlo et al., 2011).”
• Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, neutral): “Although Tet2 was recently suggested to play an important role in ES cell differentiation (Ito et al., 2010; Koh et al., 2011), EIIa-creTet2 / mice were born with the expected Mendelian ratios with normal growth and organ development.”