The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape

Abstract

Enhancers are cis-regulatory elements that play essential roles in tissue-specific gene expression during development. Enhancer function in the expression of developmental genes requires precise regulation, while deregulation of enhancer function could be the main cause of tissue-specific cancer development. MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. Importantly, large-scale DNA sequencing studies have revealed that they are amongst the most frequently mutated genes associated with human cancers. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. Recent studies have provided a better understanding of the possible mechanisms underlying the roles of MLL3/MLL4 complexes in enhancer regulation. Moreover, accumulating studies offer new insights into our knowledge of the potential role of MLL3/MLL4 in cancer development. In this review, we summarize recent evidence on the molecular mechanisms of MLL3/MLL4 in the regulation of active enhancer landscape and long-range gene expression, and discuss their clinical implications in human cancers.

ASXL1/2 mutations and myeloid malignancies

“…In mammals, six Set1-related enzymes (SET1/MLL family members)—Set1A, Set1B, and MLL1-4 (excludes MLL5)—reside in COMPASS-like complexes with the WRAD complex of proteins [WD repeat-containing protein 5 (WDR5), Absent-Small-Homeotic-2- Like protein (ASH2), Retinoblastoma Binding Protein 5 (RBBP5), and Dumpy-30 (DPY30)], which is required for methyltransferase activity, as well as additional proteins. For example, MLL3/MLL4 COMPASS also includes Nuclear Receptor Coactivator 6 (NCOA6), PA1, and the H3K27me3 demethylase Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) [ 116 , 117 ] (Fig. 4 ).…”

Identification of putative enhancer-like elements predicts regulatory networks active in planarian adult stem cells

“…In mammals, Mll3 and Mll4 are two paralogous methyltransferases of the COMPASS family (SET1/MLL) that regulate enhancer activity by mono-methylating H3K4 (Wang et al 2021). In addition, the mll3/4 methyltransferase complex associates with the histone acetyltransferase p300/CBP that mediates H3K27 acetylation at enhancers and thus gives rise to the active enhancer landscape (Wang et al 2021). The enhancer-like regions were clearly more responsive to the knockdown of Smed-lpt as compared to random points within the genome, and the response was most evident at the center of predicted enhancer-like regions (Fig.…”

“…Furthermore, we calculated the mean peak value with respect to the change in H3K4me1 signal upon RNAi-mediated Smed-lpt knockdown (corresponding to the N-terminus of mammalian mll3/4 or kmt2c/d, see Mihaylova et al 2018). In mammals, Mll3 and Mll4 are two paralogous methyltransferases of the COMPASS family (SET1/MLL) that regulate enhancer activity by mono-methylating H3K4 (Wang et al 2021). In addition, the mll3/4 methyltransferase complex associates with the histone acetyltransferase p300/CBP that mediates H3K27 acetylation at enhancers and thus gives rise to the active enhancer landscape (Wang et al 2021).…”

Single-Cell Transcriptome Analysis Defines Expression of Kabuki Syndrome-Associated KMT2D Targets and Interacting Partners

“…As part of the complex of proteins associated with histone H3 lysine 4 methyltransferase SET1 (SET1/ COMPASS), KMT2D and KDM6A physically associate with a protein module comprised of the WD-repeat protein 5 (WDR5), retinoblastoma-binding protein 5 (RBBP5), absent, small, and homeotic 2-like protein-encoding protein (ASH2L) and Dpy-30 histone methyltransferase complex regulatory subunit (DPY30) and nuclear receptor cofactor 6 (NCOA6), Pax-interacting protein 1 (PTIP), and PTIP-associated protein 1 (PA1) [6]. Recent research has shown that association of KMT2D with the histone acetyltransferases p300 and CBP encoded by EP300 and CREBBP is capable of establishing active enhancer states enriched in histone H3 lysine 4 monomethylation and histone H3 lysine 27 acetylation (H3K4me1/H3K27ac) to facilitate long-distance gene activation [9]. In addition to p300/CBP, the interplay between KMT2D and the SWI/SNF related, matrix associated, and actin-dependent ATP-dependent chromatin remodeling factors (SMARCA4 and SMARCB1) promotes cell type-specific enhancer activation [10].…”