JOURNAL ARTICLE

The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine

Jean-Pierre Etchegaray, Lukas Chavez, Yun Huang, Kenneth N Ross, Jiho Choi, Barbara Martinez-Pastor, Ryan M Walsh, Cesar A Sommer, Matthias Lienhard, Adrianne Gladden, Sita Kugel, Dafne M Silberman, Sridhar Ramaswamy, Gustavo Mostoslavsky, Konrad Hochedlinger, Alon Goren, Anjana Rao, Raul Mostoslavsky
Nature Cell Biology 2015, 17 (5): 545-57
25915124
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.

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