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- Title
The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
- Authors
Etchegaray, Jean-Pierre; Chavez, Lukas; Huang, Yun; Ross, Kenneth N.; Choi, Jiho; Martinez-Pastor, Barbara; Walsh, Ryan M.; Sommer, Cesar A.; Lienhard, Matthias; Gladden, Adrianne; Kugel, Sita; Silberman, Dafne M.; Ramaswamy, Sridhar; Mostoslavsky, Gustavo; Hochedlinger, Konrad; Goren, Alon; Rao, Anjana; Mostoslavsky, Raul
- 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.
- Subjects
HISTONE deacetylase; EMBRYONIC stem cells; FATE mapping (Genetics); SIRTUINS; CHROMOSOMAL translocation; HISTONES; METHYLCYTOSINE
- Publication
Nature Cell Biology, 2015, Vol 17, Issue 5, p545
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb3147