ausblenden:
Schlagwörter:
Acetylation
Animals
Cell Differentiation
Cell Lineage
Cells, Cultured
Chromatin Assembly and Disassembly
Cytosine/*analogs & derivatives/metabolism
DNA-Binding Proteins/genetics/*metabolism
Embryonic Stem Cells/*enzymology/pathology/transplantation
Gene Expression Regulation, Developmental
Genotype
Histones/metabolism
Homeodomain Proteins/genetics/metabolism
Humans
Induced Pluripotent Stem Cells/enzymology
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, SCID
Neurogenesis
Octamer Transcription Factor-3/genetics/metabolism
Phenotype
Proto-Oncogene Proteins/genetics/*metabolism
RNA Interference
SOXB1 Transcription Factors/genetics/metabolism
Signal Transduction
Sirtuins/deficiency/genetics/*metabolism
Teratoma/enzymology/pathology
Transfection
Zusammenfassung:
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.
