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

Article

Authorship

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 MAGALI ; Ramaswamy, Sridhar ; Mostoslavsky, Gustavo ; Hochedlinger, Konrad ; Goren, Alon ; Rao, Anjana ; Mostoslavsky, Raul

Date

2015

Publishing House and Editing Place

Nature Publishing Group

Magazine

NATURE CELL BIOLOGY., vol. 17 (pp. 545-557) Nature Publishing Group

Summary Information provided by the agent in SIGEVA

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 H3K5... 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.