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Characterising the MLL complex: epigenetic regulation of Hoxa genes

Bussiere, Marianne (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

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.

Type of Work:Ph.D. thesis.
Supervisor(s):Nightingale, Karl
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute of Biomedical Research, Chromatin and Gene Expression Group
Subjects:R Medicine (General)
Institution:University of Birmingham
ID Code:707
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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