The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Academic Article uri icon


  • 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.

published proceedings

  • Nat Cell Biol

altmetric score

  • 26

author list (cited authors)

  • Etchegaray, J., Chavez, L., Huang, Y., Ross, K. N., Choi, J., Martinez-Pastor, B., ... Mostoslavsky, R

citation count

  • 115

complete list of 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

publication date

  • April 2015