Abstract
Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. We show that the MLL1 core complex anchors to the NCP via the conserved RbBP5 and ASH2L, which interact extensively with nucleosomal DNA and the surface close to the N-terminal tail of histone H4. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, thereby facilitating symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.
Highlights
H3, and H4) and 146 base pairs of genomic DNA, represents the first level of eukaryotic DNA packaging[1]
An electrophoretic mobility shift assay (EMSA) demonstrated that MLL1RWSAD binds to the nucleosome core particles (NCPs) with modest affinity (Supplementary Fig. 1b, c and data not shown)
We found that this complex showed markedly enhanced activity for higher methylation states (i.e., H3 lysine (K) methylation (H3K4me)[2] and H3K4me3) when the NCP was used as a substrate (Fig. 1b and Supplementary Fig. 1d)
Summary
H3, and H4) and 146 base pairs of genomic DNA, represents the first level of eukaryotic DNA packaging[1]. Biochemical studies show that the core components of the MLL1 complex are able to enhance the MLL1SET activity for H3K4me[1] and H3K4me[2] by ~600-fold[19] Mechanisms underlying this stimulation has been elegantly demonstrated in several structural studies of the human MLL1/3SET-ASH2LSPRY-RbBP5330–375 subcomplex[16], the homologous yeast SET1 complexes[20,21], as well as individual MLL1 core components[22,23,24]. These previous structures of the MLL SET domains[16,25,26] were determined with either no substrate or H3 peptide as the substrate. It remains to be determined how MLL1 activity, especially the tri-methylation activity, is regulated on chromatin
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