Epigenetic regulation at MLL1 target genes

Wiersma, Maaike (2015). Epigenetic regulation at MLL1 target genes. University of Birmingham. Ph.D.

PDF - Accepted Version

Download (4MB)


The mixed-lineage leukaemia 1 protein is a histone methyl-transferase that deposits the gene activating H3K4 trimethyl mark, and is often mutated in leukaemia. MLL1 is normally associated with a cohort of cofactors, but the mechanisms regulating the histone methyl-transferase activity remain unclear. Here I examine the role of Msk1, a downstream kinase of the MAP-kinase pathway, in regulating MLL1 activity. Msk1 is known to deposit the H3S10 phosphorylation mark, which was found to stimulate MLL1’s methylation activity \(in\) \(vitro\).
Here I demonstrate that MLL1 and Msk1 can be immunoprecipitated and their patterns of genomic binding show an overlap at ~30 of sites, suggesting a direct functional interaction. In transient MLL1 and Msk1 knock-down cells, known MLL1 target genes were down-regulated and at a global level, 30% of all responding genes were regulated in the same manner. Furthermore, key histone modifications at MLL1 target genes change in Msk1 knock-down cells, suggesting that histone cross-talk within the MLL1 complex acts as a means of gene regulation. Finally, cell cycle studies suggest MLL1-Msk1 cross-talk may stimulate MLL1-driven gene expression after mitosis. These findings suggest that MLL1 is regulated by Msk1 and therefore by extracellular signals via the MAP-kinase pathway.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Biomedical Research
Funders: None/not applicable
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine
URI: http://etheses.bham.ac.uk/id/eprint/5813


Request a Correction Request a Correction
View Item View Item


Downloads per month over past year