Structural Analysis of the Ash2L/Dpy-30 Complex Reveals a Heterogeneity in H3K4 Methylation

Dpy-30 is a regulatory subunit controlling the histone methyltransferase activity of the KMT2 enzymes in vivo. Paradoxically, in vitro methyltransferase assays revealed that Dpy-30 only modestly participates in the positive heterotypic allosteric regulation of these methyltransferases. Detailed genome-wide, molecular and structural studies reveal that an extensive network of interactions taking place at the interface between Dpy-30 and Ash2L are critical for the correct placement, genome-wide, of H3K4me2 and H3K4me3 but marginally contribute to the methyltransferase activity of KMT2 enzymes in vitro. Moreover, we show that H3K4me2 peaks persisting following the loss of Dpy-30 are found in regions of highly transcribed genes, highlighting an interplay between Complex of Proteins Associated with SET1 (COMPASS) kinetics and the cycling of RNA polymerase to control H3K4 methylation. Overall, our data suggest that Dpy-30 couples its modest positive heterotypic allosteric regulation of KMT2 methyltransferase activity with its ability to help the positioning of SET1/COMPASS to control epigenetic signaling. •Dpy-30 marginally contributes to the enzymatic activity of KMT2 enzymes in vitro•A tryptophan on Ash2L makes key hydrophobic contacts with Dpy-30•Blocking Dpy-30/Ash2L interaction perturbs H3K4 methylation in vivo•H3K4me2 and H3K4me3 peaks are differentially affected by the loss of Dpy-30 Haddad et al. highlight that several interactions help in the formation of the Ash2L/Dpy-30 complex. The study also demonstrates that Dpy-30 couples its marginal ability to allosterically regulate KMT2 enzymes and chromatin recruitment activity to control epigenetic signaling in vivo.