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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Author and article information

Journal

Journal ID (iso-abbrev): Nat. Cell Biol.

Title: Nature cell biology

Publisher: Springer Nature

ISSN (Electronic): 1476-4679

ISSN (Print): 1465-7392

Publication date (Electronic): May 2015

Volume: 17

Issue: 5

Affiliations

[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.

Article

Publisher Item ID: ncb3147 Mid ID: NIHMS725229

DOI: 10.1038/ncb3147

PMC ID: 4593707

PubMed ID: 25915124

SO-VID: d6a889ec-7c1b-496b-abb0-fff7b461a0f7

History

Data availability:

Comments

Comment on this article

scite_

Cited by 73

See all cited by

- Version 1