H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes

Abstract

In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.

The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes

“…1 ). Only KMT2G does not require uH2B to form H3K4me3 in an in vitro reconstituted chromatin system [ 28 ] (Table 1 ). Our group has previously shown that the ubiquitination of H2B is dependent on transcription [ 29 ].…”

Construction of a prognostic model with histone modification-related genes and identification of potential drugs in pancreatic cancer

“…DPY30, regarded as the core unit of the risk signature, is a common essential subunit of all Set1/MLL complexes and facilitates H3K4 methylation in cells [ 28 , 29 ]. The WDR5, RbBP5, ASH2L, and DPY30 are collectively called WRAD, which make Set1/MLL complexes capable of di- and tri-methylation activities [ 30 ], while MLL by itself is a mono-methyltransferase [ 31 ].…”

“…Therefore, their relationship with each other is actually the cross-linking interaction between various histone modifications. Among the four target genes, CBX8 is involved in the ubiquitination of H2AK119 as part of polycomb repressive complex 1 (PRC1) [ 36 ], DPY30 is involved in the methylation of H3K4 as part of SET1/MLL complex [ 28 , 29 ], and PADI1 is involved in the citrullination of H4R3 and H3R2/8/17 [ 61 ]. They are one of the factors that maintain the homeostasis of histone modifications in the body, or near certain tumor-related genes.…”

The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer

“…MLL3 and MLL4 monomethylate H3K4 located at the enhancer regions involved in cell type-specific gene expression [ 22 , 23 , 24 , 25 ]. Recent studies have revealed that the activity of KMT complexes is stimulated by the monoubiquitylation of histone H2B, and that distinct subunits components may have a role in determining the levels and state of H3K4 methylation [ 26 , 27 , 28 ].…”