Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4

Abstract

Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers.

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

“…These observations are consistent with recent studies showing that COMPASS-like MLL3/ MLL4 complexes predominantly monomethylate H3K4 at enhancer regions and specific promoter regions (Herz et al 2012;Hu et al 2013;Morgan and Shilatifard 2013;Cheng et al 2014). Interestingly, upon incubation of the MLL3 SET domain with the Ash2L/RbBP5 complex reconstituted with RbBP5 phos , peaks corresponding to H3K4me1 and H3K4me2 were observed.…”

“…MLL1/MLL2 di/trimethylate H3K4 (H3K4me2/3) and regulate Hox gene expression during embryonic development (Yu et al 1995;Dou et al 2006). MLL3/MLL4 regulate adipogenesis ) and primarily monomethylate H3K4 (H3K4me1) at both enhancer (Herz et al 2012;Hu et al 2013) and promoter (Cheng et al 2014) regions, while SET1A/B are the primary H3K4 trimethyltransferases (Wu et al 2008). However, despite divergence in catalytic activity and functional roles, enzymes of the KMT2/COMPASS family must assemble into multisubunit complexes to carry out their biological functions.…”

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…Nevertheless, our group and others have observed both global and local changes in H3K4me3 at promoters of genes with cancer-promoting activity, in cancer cells (14,25,26,53,54). Methylation of H3K4 is primarily catalyzed by TrxG members, with the modification of H3K4me3 chiefly catalyzed by hSETD1A (26,27,(55)(56)(57)(58). Here, we showed increase in both global H3K4me3 and hSETD1A protein levels in cultured breast cancer cell lines (Fig.…”

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…Using the example of 786-O cells, at least two other mutations in these cells may have a direct impact on chromatin-MLL3 (p.A3902G) and gain-of-function TP53 mutations (p.R248W). MLL3, a histone 3 lysine 4 methyltransferase, is directly responsible for formation of the H3K4me1 enhancer mark (89,90) and plays a critical role for enhancer regulation (91). Gain-of-function TP53 mutants also bind aberrantly to chromatin, especially near methyltransferases MLL1 and MLL2, potentially contributing to tumor growth via chromatin deregulation (92).…”