Etchegaray, Jean-PierreChavez, LukasHuang, YunRoss, Kenneth NChoi, JihoMartinez-Pastor, BarbaraWalsh, Ryan MSommer, Cesar ALienhard, MatthiasGladden, AdrianneKugel, SitaSilberman, Dafne MRamaswamy, SridharMostoslavsky, GustavoHochedlinger, KonradGoren, AlonRao, AnjanaMostoslavsky, Raul2025-01-312025-01-312015-05https://hdl.handle.net/20.500.12105/26217How 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.enghttp://creativecommons.org/licenses/by-nc-nd/4.0/research articleAttribution-NonCommercial-NoDerivatives 4.0 International25915124https://pmc.ncbi.nlm.nih.gov/articles/PMC4593707/pdf/nihms725229.pdfopen access