Coordinated regulation of cellular identity–associated H3K4me3 breadth by the COMPASS family

Abstract

Set1A and Set1B, two members of the COMPASS family of methyltransferases that methylate the histone H3 lysine 4 (H3K4) residue, have been accredited as primary depositors of global H3K4 trimethylation (H3K4me3) in mammalian cells. Our previous studies in mouse embryonic stem cells (ESCs) demonstrated that deleting the enzymatic SET domain of Set1A does not perturb bulk H3K4me3, indicating possible compensatory roles played by other COMPASS methyltransferases. Here, we generated a series of ESC lines harboring compounding mutations of COMPASS methyltransferases. We find that Set1B is functionally redundant to Set1A in implementing H3K4me3 at highly expressed genes, while Mll2 deposits H3K4me3 at less transcriptionally active promoters. While Set1A-B/COMPASS is responsible for broad H3K4me3 peaks, Mll2/COMPASS establishes H3K4me3 with narrow breadth. Additionally, Mll2 helps preserve global H3K4me3 levels and peak breadth in the absence of Set1A-B activity. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity.

SETD1B controls cognitive function via cell type specific regulation of neuronal identity genes

“…These data may suggest that H3K4 KTM's other than Setd1b are essential to ensure the sufficient expression of genes important for basal cellular processes in neurons, while Setd1 enables to preeminent expression of neuronal identity genes. This view is in line with a recent study in mouse embryonic stem cells in which Setd1b was associated with the expression of highly expressed genes that exhibit a broad H3K4me3 peak, while Kmt2b was linked to the expression of genes with narrow H3K4me3 peaks (Sze et al, 2020). Interestingly, this study suggested a functional redundancy of Setd1b and Setd1a.…”

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

“…However, there is a confusion with the nomenclature between MLL2 and MLL4 [ 7 , 17 ]. The current literature indicates that KMT2F and KMT2G complexes catalyze all three states of methylation and are responsible for most of H3K4 trimethylation including that at the broad H3K4me3 domains, while KMT2A-D produces mono- and/or di-methyl H3K4 [ 17 – 22 ] (Table 1 ). In one of these studies, H3K4 methyl forms were determined by mass spectrometry [ 19 ], circumventing the issue of frequent cross-reactivity of many H3K4me3 antibodies with H3K4me1 or H3K4me2 [ 23 ].…”

Analyzing the impact of CFP1 mutational landscape on epigenetic signaling

“…46 Interestingly, a recent study found that SETD1A/B complexes establish broad H3K4me3 peaks at highly expressed genes while MLL2 establishes narrow H3K4me3 peaks at promoter regions of lowly transcribed genes to maintain cell identity of embryonic stem cells (ESCs). 47 Intriguingly, the same authors demonstrated that in the absence of SETD1A/B in ESCs, H3K4me3 is maintained by MLL2, suggesting that these enzymes share some overlapping functions. The idea was further confirmed recently in mouse oocyte.…”

“…MLL3/MLL4 mainly catalyze H3K4me1 at enhancer regions, SETD1A/B maintain global H3K4me3 and MLL1/MLL2 deposit the same modification in a locus‐specific manner 46 . Interestingly, a recent study found that SETD1A/B complexes establish broad H3K4me3 peaks at highly expressed genes while MLL2 establishes narrow H3K4me3 peaks at promoter regions of lowly transcribed genes to maintain cell identity of embryonic stem cells (ESCs) 47 …”