Bussiere, Marianne (2010)
Ph.D. thesis, University of Birmingham.
The Mixed-Lineage Leukaemia (MLL1) protein is a key developmental factor that acts to regulate genes via its histone methyl-transferase activity. This study aimed to examine how MLL1 and its associated complex contribute to gene regulation in a functionally relevant cell background. To assess dynamic processes involved, we developed a haematopoietic Stem Cell (hSC) -based system, in which Hoxa genes are down-regulated in a differentiation- induced manner. I characterised the histone modification distribution on two MLL-target genes showing the largest changes upon differentiation: Hoxa4 and Hoxa5. When active, these genes are associated with a peak of “activating” histone marks (H3K4me3, H3K9ac, H4K16ac) over the transcriptional start site, which are lost when the gene is repressed. This correlated with the recruitment of enzymes that deposit these marks, including components of the MLL complex (MLLC, MLLN and menin) as well as HATs that may be associated with the complex (CBP and MOF). Interestingly, the location of these proteins does not always correlate with the marks they deposit. We show that the dual mark H3K9acS10p is present on active Hoxa4 and Hoxa5 genes, and correlates with the presence of the histone kinase Msk1. We speculate that Msk1 contributes to regulating MLL1 HMT’ase activity on these genes.
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