Crosstalk with H3K4 methylation. (A) Bivalent promoters comarked with H3K27me3 and H3K4me3 are abundant in ESCs, in which they are temporarily repressed but are later resolved into monovalent promoters possessing either the active H3K4me3 mark or the repressive H3k27me3 mark. Despite this general trend, differentiated cells also possess bivalent promoters, and this resolution is not always absolute; transcription activity depends on the relative levels of H3K4me3 of H3K27me3 (Jadhav et al., 2016, 2020). (B) While the H3K4me3 mark deposited by KMT2A/B is antagonistic to the H3K27me3 mark deposited by PRC2 at bivalent promoters, KMT2A/B is more robustly recruited to active monovalent promoters by its MEN1 accessory factor. MEN1 inhibition or KO thus augments KMT2A/B recruitment to bivalent promoters and promotes gene repression. PRC2 inhibition has the same effect on bivalent promoters, and the combined inhibition of PRC2 and MEN1 leads to more effective activation of bivalent promoters (Sparbier et al., 2023).