Rotational dynamics of the MLL complex on nucleosome and its implication in heterogeneity of the epigenetic landscape

Abstract

The MLL family histone methyltransferases deposit mono‐, di‐, tri‐methylation of histone H3 lysine 4 (H3K4me). Epigenomic studies highlight the discrete distribution of H3K4me3 and H3K4me1 at gene promoters and distal enhancers, respectively. However, how this is achieved remains unclear. We have performed single particle cryo‐EM studies for the MLL1 core complex on the nucleosome core particles (NCP). We revealed a surprisingly dynamic nature of the MLL1 complex on the NCP. We show that DPY30 and the intrinsically disordered regions (IDRs) of ASH2L work together to restrict the rotational dynamics of the MLL1 complex, which is necessary for dramatic increase of processivity and activity of the MLL1 complex. The DPY30 and ASH2L‐IDR dependent regulation applies to all members of the MLL/SET1 family enzymes. We further show that DPY30 is causal for de novo establishment of H3K4me3 in cells and its preferred localization at gene promoters may be the primary reason for selective enrichment of H3K4me3. Our study provides a new paradigm of how discrete H3K4me state is regulated on chromatin.