Abstract
This study assesses changes in activator and repressor modifications to histones associated with the core transcription factor genes most highly upregulated or downregulated in pancreatic β-cells relative to expression in an embryonic stem cell line. Epigenetic analysis of the Oct4, Utf1, Nanog and Sox2 (pluripotency) and Pdx1, Nkx6.1, Nkx2.2 and MafA (pancreatic β-cells) transcription factor genes in embryonic stem cells and a β-cell line (MIN6) showed the pluripotency genes were enriched for active (histone 3 trimethylated at lysine 4 and histone 3 acetylated at lysine 9) and depleted of repressor modifications (histone 3 trimethylated at lysine 27 and histone 3 trimethylated at lysine 9) around the transcription start site in mouse embryonic stem cells (D3), and this was reversed in MIN6 cells. The β-cell transcription factors were bivalently enriched for activating (histone 3 trimethylated at lysine 4) and repressor (histone 3 trimethylated at lysine 27) modifications in embryonic stem cells but were monovalent for the activator modification (histone 3 trimethylated at lysine 4) in the β-cells. The polycomb repressor complex 2 acts as a histone 3 lysine 27 methylase and an essential component of this complex, SUZ12, was enriched at the β-cell transcription factors in embryonic stem cells and was reduced MIN6. Knock-down of SUZ12 in embryonic stem cells, however, did not reduce the level of histone 3 trimethylated at lysine 27 at β-cell transcription factor loci or break the transcriptional repression of these genes in embryonic stem cells. This study shows the reduction in the total SUZ12 level was not a sufficient cause of the resolution of the epigenetic bivalency of β-cell transcription factors in embryonic stem cells.
Highlights
There is a marked difference in the pattern of transcription from the genome between pluripotent cells (as exemplified by embryonic stem cells (ES cells) and each of the range of differentiated cell types that make up the body [1,2,3]
Categorization according to the three parent Gene Ontology (GO) domains found that of the genes upregulated in MIN6 relative to D3 cells, 71.3% were associated with biological processes, 7.4% with molecular function and 21.3% with cellular components
This study shows that a range of core transcription factors that define the pluripotent state are characterized by an active epigenetic signature in ES cells and have a characteristic repressive epigenetic signature in the MIN6 b-cell insulinoma line
Summary
There is a marked difference in the pattern of transcription from the genome between pluripotent cells (as exemplified by embryonic stem cells (ES cells) and each of the range of differentiated cell types that make up the body [1,2,3]. The pluripotent state requires the expression of a core set of transcription factors that include NANOG, POU5F1 (hereafter known as OCT4), UTF1 and SOX2 [4,5]. Differentiation from the pluripotent state is accompanied by the repression of these core transcription factors and the active expression of different sets of transcription factors. Acetylation of H3K9 (H3K9ac) and tri-methylation of H3K4 (H3K4me3) are associated with an open, euchromatin structure that permits easier access of transcription factors and the activation of gene transcription [8,9,10]. H3K27 and H3K9 tri-methylation (H3K27me and H3K9me3) generally serve as repressive chromatin modifications by the creation of a more closed conformation and these modifications are commonly associated with the formation of repressive heterochromatin [11,12]
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