Abstract
BackgroundThe KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET domain-catalysed methylation of H3K4. It is essential for normal embryonic development and haematopoiesis and frequently mutated in cancer. The catalytic properties and targeting of KMT2A/MLL1 depend on the proteins with which it complexes and the post-translational protein modifications which some of these proteins put in place, though detailed mechanisms remain unclear.ResultsKMT2A/MLL1 (both native and FLAG-tagged) and Msk1 (RPS6KA5) co-immunoprecipitated in various cell types. KMT2A/MLL1 and Msk1 knockdown demonstrated that the great majority of genes whose activity changed on KTM2A/MLL1 knockdown, responded comparably to Msk1 knockdown, as did levels of H3K4 methylation and H3S10 phosphorylation at KTM2A target genes HoxA4, HoxA5. Knockdown experiments also showed that KMT2A/MLL1 is required for the genomic targeting of Msk1, but not vice versa.ConclusionThe KMT2A/MLL1 complex is associated with, and functionally dependent upon, the kinase Msk1, part of the MAP kinase signalling pathway. We propose that Msk1-catalysed phosphorylation at H3 serines 10 and 28, supports H3K4 methylation by the KMT2A/MLL1 complex both by making H3 a more attractive substrate for its SET domain, and improving target gene accessibility by prevention of HP1- and Polycomb-mediated chromatin condensation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0103-3) contains supplementary material, which is available to authorized users.
Highlights
The KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET domain-catalysed methylation of H3K4
KMT2A and Msk1 are physically associated in various cell lines The in vitro methylation of H3K4 by the KMT2A/MLL1 SET domain is strongly enhanced by phosphorylation of the histone peptide substrate at serine 10 [33], raising the possibility that phosphorylation of this residue may influence the gene regulatory activity of the KMT2A/MLL1 complex in vivo
Phosphorylation of H3S10 in chromatin can occur through the action of the closely related kinases Msk1 and Msk2 [35, 36], so we explored the possibility that Msk1 might operate as part of the KMT2A/MLL1 complex
Summary
The KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET domain-catalysed methylation of H3K4. The human KMT2 proteins (formerly known as mixedlineage leukaemia, MLL proteins) are highly conserved, SET domain-containing lysine methyltransferases, homologous to the Drosophila trithorax group proteins TRX (trithorax), TRR (TRX-related) and dSET1 [1, 2] Like their Drosophila homologues, they maintain and enhance the activity of genes with key roles in Wiersma et al Epigenetics & Chromatin (2016) 9:52 proteins enhance the weak catalytic activity of recombinant KMT2 by 50–500-fold [8, 9]. Only KMT2A/B complexes contain multiple endocrine neoplasia type 1 (MENIN) [10] and lens epithelium-derived growth factor (LEDGF) [11] These proteins seem to mediate interaction with transcription factors such as oestrogen receptor [12] and influence gene targeting. It is likely that these variable protein associations make a major contribution to the catalytic properties and gene regulation profiles of the three KMT2 subgroups
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