Stower, Hannah Mary (2009)
Ph.D. thesis, University of Birmingham.
Histone modifications have been closely associated with changing levels of gene expression, but their role in determining, or possibly predicting, patterns of expression is uncertain. Here, the link between histone modifications and Hoxb gene expression in mouse embryonic stem (ES) cells was explored. Levels of the “active” modifications H3K9ac and H3K4me3 at Hoxb promoters varied widely from gene to gene, but were closely correlated in ES cells. Contrastingly, the repressive modification H3K27me3 was found at equivalent levels across the cluster. Treatment with the histone deacetylase inhibitor valproate induced a coordinate increase in the levels of H3K9ac and H3K4me3 at all Hoxb promoters, but not other genes, whilst H3K27me3 was unaffected. Such increases were not maintained upon removal of the inhibitor. All Hoxb genes were silent in undifferentiated ES cells, but expression was activated at defined times of differentiation in the expected 3’ to 5’ sequence. The valproate induced increase in active modifications did not induce Hoxb expression from the cluster in undifferentiated cells, nor was there any major shift in the timing of Hoxb expression in cells transiently exposed to valproate (ie. hyperacetylated) during the start of differentiation. Thus, active histone modifications at the Hox genes are uncoupled from transcription.
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