Post translational modifications (PTMs) of histone tails are an important determinant of chromatin structure, and can act as key regulators of DNA-dependent processes. Methylation of histone 3 at lysine 4 (H3K4) is one of the most widely studied PTMs because of its correlation with transcription. Three methylation states exist at H3K4: mono-, di, and tri-methylation (H3K4me1, -me2, and -me3, respectively). Each methylation state occupies a distinct genomic position, supporting the view that the extent of methylation at H3K4 has a functional significance. However, the exact biological function of these three marks are not well understood. H3K4 methylation is written by SET domain-containing enzymes that function within SET/COMPASS/MLL complexes. Our lab has previously identified the SET-16 enzyme as writing H3K4me3 in C. elegans. The other well-characterised H3K4-specific methyl transferases in the worm is SET-2, an enzymes responsible for bulk H3K4me2/me3 levels. Using targeted RNAi screens, we have characterised the full landscape of SET domain enzymes affecting all three methylation states at H3K4 during embryogenesis in C. elegans (Chapter 3). Unexpectedly, many previously uncharacterised enzymes were identified as preferentially affecting each of the methylation states, including SET-19 that can deposit all three marks, and several candidates that preferentially affect H3K4me1: SET-30, SET-27, MES-2, and MES-4. During the project, Greer et al. 2014 independently identified two enzymes with activities targeting H3K4, SET-17 and SET-30, which were also candidates from our RNAi screens. With a focus on enzymes acting on H3K4me1, we demonstrate that H3K4me1 candidates can show different patterns of temporal regulation and also have roles in regulating soma versus germline cell-fate decisions (Chapter 4). Finally, we demonstrate a novel role for MES-2 (a methyltransferase enzyme with a highly conserved role in depositing repressive H3K27 methylation) in acting alongside the SPR-5 H3K4me2 demethylase to regulate levels of H3K4me1 during embryogenesis (Chapter 5).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:694318 |
| Date | January 2016 |
| Creators | Wilkins, Elizabeth |
| Contributors | Whitmarsh, Alan ; Poulin, Gino |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/expanding-the-network-of-enzymes-affecting-methylation-ath3k4-histone-3-lysine-4-during-caenorhabditis-elegansembryogenesis(ed012cfc-e1eb-4cff-bf0c-71522826f172).html |
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