Nuclear architectural aspects of the histone 3 lysine 4 methyltransferase subclass of trithorax-Group action

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Epigenetic regulation exerted by the trithorax-Group (trxG) includes methylation of lysine 4 on the histone 3 tail, which is the epigenetic modification that best characterizes active chromatin. In particular trimethylation of histone 3 lysine 4 (H3K4me3) is universally found on nucleosomes at active promoters and the enzyme complexes that deposit this methylation are amongst the most conserved components in eukaryotic epigenetic regulation. Mammals have six H3K4 methyltransferases (MTs) and they are all large proteins including the largest known nuclear protein, Mll4. Despite the fact most of the protein is composed of low complexity sequence and the MT enzyme module is confined to only a small section at the very C-terminus, the large sizes of these proteins are conserved in evolution. The potential for these large proteins to organise genome architecture has not been examined and is the basis for this project. We aim to combine our expertise in engineering embryonic stem cells and ongoing progress in H3K4 MT research with recent technological improvements in (i) single protein detection and tracking in live cell nuclei; and (ii) 4C, Hi-C and single cell Hi-C to evaluate the proposition that the H3K4 MT system regulates an aspect of genome architecture. Embryonic stem cells will be the functional venue. The roles of the H3K4 MTs as bookmarking factors for the re-establishment of genome architecture after mitosis and the relationship between epigenetic priming and genome architecture during differentiation towards neural lineages will be investigated.