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Nat Cell Biol. 2015 May;17(5):545-57. doi: 10.1038/ncb3147. Epub 2015 Apr 27.

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

Author information

1
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
2
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92037, USA.
3
The Center for Regenerative Medicine (CReM), Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
4
Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
5
Department of Human Biochemistry, Medical School, CEFyBO-UBA-CONICET, Buenos Aires, CP1121, Argentina.
6
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

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.

PMID:
25915124
PMCID:
PMC4593707
DOI:
10.1038/ncb3147
[Indexed for MEDLINE]
Free PMC Article

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