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. Epub 2015 Apr 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Acetylation
  • Animals
  • Cell Differentiation*
  • Cell Lineage*
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / enzymology*
  • Embryonic Stem Cells / pathology
  • Embryonic Stem Cells / transplantation
  • Gene Expression Regulation, Developmental
  • Genotype
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / enzymology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Nanog Homeobox Protein
  • Neurogenesis
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Phenotype
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction
  • Sirtuins / deficiency
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Teratoma / enzymology
  • Teratoma / pathology
  • Transfection

Substances

  • DNA-Binding Proteins
  • Histones
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • TET1 protein, mouse
  • Tet2 protein, mouse
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Sirt6 protein, mouse
  • SIRT6 protein, human
  • Sirtuins