The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
Publication type | Journal Article
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Authors | |
Keywords | |
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. |
Year of Publication | 2015
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Journal | Nat Cell Biol
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Volume | 17
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Issue | 5
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Pages | 545-57
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Date Published | 2015 May
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ISSN | 1476-4679
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URL | |
DOI | 10.1038/ncb3147
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PubMed ID | 25915124
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PubMed Central ID | PMC4593707
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Grant list | 5R01HD058013-05 / HD / NICHD NIH HHS / United States
R01 GM093072 / GM / NIGMS NIH HHS / United States
HD065812 / HD / NICHD NIH HHS / United States
R01 HD065812 / HD / NICHD NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 CA151535 / CA / NCI NIH HHS / United States
CA151535 / CA / NCI NIH HHS / United States
R01 HD058013 / HD / NICHD NIH HHS / United States
DK088190-01A1 / DK / NIDDK NIH HHS / United States
R01 DK088190 / DK / NIDDK NIH HHS / United States
GM093072-01 / GM / NIGMS NIH HHS / United States
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