Journal Article

DKFZ-2017-02518

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.

Etchegaray, J.-P. ; Chavez, L.DKFZ* ; Huang, Y. ; Ross, K. N. ; Choi, J. ; Martinez-Pastor, B. ; Walsh, R. M. ; Sommer, C. A. ; Lienhard, M. ; Gladden, A. ; Kugel, S. ; Silberman, D. M. ; Ramaswamy, S. ; Mostoslavsky, G. ; Hochedlinger, K. ; Goren, A. ; Rao, A. ; Mostoslavsky, R.

2015
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/ncb3147

Abstract: 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.

Keyword(s): DNA-Binding Proteins ; Histones ; Homeodomain Proteins ; Nanog Homeobox Protein ; Nanog protein, mouse ; Octamer Transcription Factor-3 ; Pou5f1 protein, mouse ; Proto-Oncogene Proteins ; SOXB1 Transcription Factors ; Sox2 protein, mouse ; TET1 protein, mouse ; Tet2 protein, mouse ; 5-hydroxymethylcytosine ; Cytosine ; Sirt6 protein, mouse ; SIRT6 protein, human ; Sirtuins

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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