Crosstalk with H3K36 methylation. (A) Although PCL1/2/3 all possess a Tudor domain that recognizes H3K36me3, H3K36me2/3 inhibits EZH2 catalytic activity, and thus H3K27me3 and H3K36me2/3 usually do not colocalize. PCL3 is unique in that it was shown to be able to recruit NO66, a H3K36me2/3 demethylase, and thus could potentially help to initiate PRC2-mediated repression of hitherto H3K36me2/3 marked, actively transcribed genes. (B) The oncohistone H3K27M inhibits PRC2 activity and thus depletes H3K27me3 at weak PRC2 targets. Invasion of H3K36me2, which is deposited by NSD1/2, into these regions results in transcription activation, which is mediated at least in part by LEDGF and HDGF2. (C)NSD1/2 double KO largely recapitulates the effect of H3K36M overexpression in that they both deplete intergenic H3K36me2, resulting in redistribution of PRC2 from their canonical targets to intergenic regions and non-canonical genic targets and hence their up- and downregulation, respectively (Rajagopalan et al., 2021). (D) H3K36me2 depletion improves iPSC induction efficiency by promoting the simultaneous silencing of mesenchymal genes and activation of epithelial/pluripotency genes. Epithelial/pluripotency gene activation depends on the DNA hypomethylation facilitated by reduced DNMT3A/B recruitment and increased TET activity. Loss of H3K36me2 promotes PRC2 recruitment and thus silencing of mesenchymal genes (Hoetker et al., 2023). Additionally, the catalytic-independent activity of TET1 (Chrysanthou et al., 2022) may also contribute to PRC2 recruitment.