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

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. He...

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Detalles Bibliográficos
Autores: 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 Magalí, Ramaswamy, Sridhar, Mostoslavsky, Gustavo, Hochedlinger, Konrad, Goren, Alon, Rao, Anjana, Mostoslavsky, Raul
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/45155
Acceso en línea:http://hdl.handle.net/11336/45155
Access Level:acceso abierto
Palabra clave:SITR6
STEM CELLS
DEVELOPMENT
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
Descripción
Sumario: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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