Role of Tet proteins in 5mC to 5hmC conversion, ES cell self-renewal, and ICM specification

By Shinsuke Ito, A. D’Alessio, O. Taranova, Kwonho Hong, L. Sowers, Yi Zhang. Nature, 2010

2,467 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a9bfc67f09937f50bb886780a3d00454e564948c

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In Molecular Biology

1. Hao Wu
2. Yi Zhang
3. Chuan He
4. A. Bird
5. Christoph Bock
6. Hongjun Song
7. Guo-li Ming
8. Peter A. Jones

Citations in the corpus

• Cancer epigenetics reaches mainstream oncology (2011, background): “It will be necessary to gain insight into the role of this recently described modification, detected in ES cells and Purkinje neurons and involved in ES cell self renewal and embryonic inner cell mass specificatio”
• Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation (2010, background): “TET2 has the classical features of an aKG-Fe(II) dioxygenase, and requires aKG in order to mediate 5-methylcytosine hydroxylation (Ito et al., 2010; Tahiliani et al., 2009).”
• 5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging (2011, background): “5-methylcytosine (5-mC) has generally been viewed as a stable covalent modification to DNA; however, the fact that 5-mC can be enzymatically modified to 5-hmC by Tet family proteins through Fe(II) α-KG–dependent hydroxylation yields a new perspective on the previously observed plasticity in 5-mC–dep”
• DNA Demethylation Dynamics (2011, background): “…putative function of both 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;…”
• Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation (2012, methodology): “Human EGLN1, 2 and 3, collagen P4H-I and FIH, and murine Tet1 and Tet2 were produced in insect cells and purified as described earlie”
• 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, positive): “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.”
• In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions (2011, background): “However, our RNA-seq analyses indicate that loss of KAP1 results in a marked downregulation of TET1 (data not shown), a major DNA demethylating enzyme (Ito et al., 2010).”
• WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, positive): “The MeDIP and hMeDIP assays were performed as previously described (Ito et al., 2010; Mohn et al., 2009).”