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

  • Nat Cell Biol. 2015 May;17(5):545-57. doi: 10.1038/ncb3147.
Jean-Pierre Etchegaray  1 ,  Lukas Chavez  2 ,  Yun Huang  2 ,  Kenneth N Ross  1 ,  Jiho Choi  1 ,  Barbara Martinez-Pastor  1 ,  Ryan M Walsh  1 ,  Cesar A Sommer  3 ,  Matthias Lienhard  2 ,  Adrianne Gladden  4 ,  Sita Kugel  1 ,  Dafne M Silberman  5 ,  Sridhar Ramaswamy  1 ,  Gustavo Mostoslavsky  3 ,  Konrad Hochedlinger  6 ,  Alon Goren  4 ,  Anjana Rao  2 ,  Raul Mostoslavsky  1
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.
PMID: 25915124 DOI: 10.1038/ncb3147
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.