The histone deacetylase SIRT6 controls embryonic stem cell fate via 
TET-mediated production of 5-hydroxymethylcytosine

Etchegaray, J. P.; Chavez, L.; Huang, Y.; Ross, K. N.; Choi, J.; Martinez-Pastor, B.; Walsh, R. M.; Sommer, C. A.; Lienhard, M.; Gladden, A.; Kugel, S.; Silberman, D. M.; Ramaswamy, S.; Mostoslavsky, G.; Hochedlinger, K.; Goren, A.; Rao, A.; Mostoslavsky, R.

doi:10.1038/ncb3147

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The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine

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Lienhard, M.
Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD ;

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Etchegaray, J. P., Chavez, L., Huang, Y., Ross, K. N., Choi, J., Martinez-Pastor, B., et al. (2015). The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nature Cell Biology, 17(5), 545-557. doi:10.1038/ncb3147.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-3AD8-8

Abstract

How embryonic stem cells (ESCs) commit to specific cell lineages and yield all cell types of a fully formed organism remains a major question. ESC differentiation is accompanied by large-scale histone and DNA modifications, but the relations between these epigenetic categories are not understood. Here we demonstrate the interplay between the histone deacetylase sirtuin 6 (SIRT6) and the ten-eleven translocation enzymes (TETs). SIRT6 targets acetylated histone H3 at Lys 9 and 56 (H3K9ac and H3K56ac), while TETs convert 5-methylcytosine into 5-hydroxymethylcytosine (5hmC). ESCs derived from Sirt6 knockout (S6KO) mice are skewed towards neuroectoderm development. This phenotype involves derepression of OCT4, SOX2 and NANOG, which causes an upregulation of TET-dependent production of 5hmC. Genome-wide analysis revealed neural genes marked with 5hmC in S6KO ESCs, thereby implicating TET enzymes in the neuroectoderm-skewed differentiation phenotype. We demonstrate that SIRT6 functions as a chromatin regulator safeguarding the balance between pluripotency and differentiation through Tet-mediated production of 5hmC.