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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Methylcytosine / analogs & derivatives
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Acetylation
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Animals
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Cell Differentiation*
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Cell Lineage*
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Cells, Cultured
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Chromatin Assembly and Disassembly
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Cytosine / analogs & derivatives*
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Cytosine / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dioxygenases
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Embryonic Stem Cells / enzymology*
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Embryonic Stem Cells / pathology
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Embryonic Stem Cells / transplantation
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Gene Expression Regulation, Developmental
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Genotype
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Histones / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Induced Pluripotent Stem Cells / enzymology
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Nanog Homeobox Protein
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Neurogenesis
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Phenotype
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Interference
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Sirtuins / deficiency
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Sirtuins / genetics
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Sirtuins / metabolism*
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Teratoma / enzymology
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Teratoma / pathology
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Transfection
Substances
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DNA-Binding Proteins
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Histones
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Homeodomain Proteins
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Nanog Homeobox Protein
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Nanog protein, mouse
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Octamer Transcription Factor-3
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Pou5f1 protein, mouse
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Proto-Oncogene Proteins
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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TET1 protein, mouse
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5-hydroxymethylcytosine
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5-Methylcytosine
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Cytosine
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Dioxygenases
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Tet2 protein, mouse
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Sirt6 protein, mouse
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SIRT6 protein, human
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Sirtuins