| Literature DB >> 25915124 |
Jean-Pierre Etchegaray1, Lukas Chavez2, Yun Huang2, Kenneth N Ross1, Jiho Choi1, Barbara Martinez-Pastor1, Ryan M Walsh1, Cesar A Sommer3, Matthias Lienhard2, Adrianne Gladden4, Sita Kugel1, Dafne M Silberman5, Sridhar Ramaswamy1, Gustavo Mostoslavsky3, Konrad Hochedlinger6, Alon Goren4, Anjana Rao2, Raul Mostoslavsky1.
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.Entities:
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Year: 2015 PMID： 25915124 PMCID： PMC4593707 DOI： 10.1038/ncb3147
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824