TY  - JOUR
AU  - Etchegaray, Jean-Pierre
AU  - Chavez, Lukas
AU  - Huang, Yun
AU  - Ross, Kenneth N
AU  - Choi, Jiho
AU  - Martinez-Pastor, Barbara
AU  - Walsh, Ryan M
AU  - Sommer, Cesar A
AU  - Lienhard, Matthias
AU  - Gladden, Adrianne
AU  - Kugel, Sita
AU  - Silberman, Dafne M
AU  - Ramaswamy, Sridhar
AU  - Mostoslavsky, Gustavo
AU  - Hochedlinger, Konrad
AU  - Goren, Alon
AU  - Rao, Anjana
AU  - Mostoslavsky, Raul
TI  - The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
JO  - Nature cell biology
VL  - 17
IS  - 5
SN  - 1476-4679
CY  - New York, NY
PB  - Nature America
M1  - DKFZ-2017-02518
SP  - 545 - 557
PY  - 2015
AB  - 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.
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Histones (NLM Chemicals)
KW  - Homeodomain Proteins (NLM Chemicals)
KW  - Nanog Homeobox Protein (NLM Chemicals)
KW  - Nanog protein, mouse (NLM Chemicals)
KW  - Octamer Transcription Factor-3 (NLM Chemicals)
KW  - Pou5f1 protein, mouse (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - SOXB1 Transcription Factors (NLM Chemicals)
KW  - Sox2 protein, mouse (NLM Chemicals)
KW  - TET1 protein, mouse (NLM Chemicals)
KW  - Tet2 protein, mouse (NLM Chemicals)
KW  - 5-hydroxymethylcytosine (NLM Chemicals)
KW  - Cytosine (NLM Chemicals)
KW  - Sirt6 protein, mouse (NLM Chemicals)
KW  - SIRT6 protein, human (NLM Chemicals)
KW  - Sirtuins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25915124
C2  - pmc:PMC4593707
DO  - DOI:10.1038/ncb3147
UR  - https://inrepo02.dkfz.de/record/126489
ER  -