Genomic location of PRMT6-dependent H3R2 methylation is linked to the transcriptional outcome of associated genes

Protein arginine methyltransferase 6 (PRMT6) catalyzes asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a). This mark has been reported to associate with silent genes. Here, we use a cell model of neural differentiation, which upon PRMT6 knockout exhibits proliferation and differentiation defects. Strikingly, we detect PRMT6-dependent H3R2me2a at active genes, both at promoter and enhancer sites. Loss of H3R2me2a from promoter sites leads to enhanced KMT2A binding and H3K4me3 deposition together with increased target gene transcription, supporting a repressive nature of H3R2me2a. At enhancers, H3R2me2a peaks co-localize with the active enhancer marks H3K4me1 and H3K27ac. Here, loss of H3R2me2a results in reduced KMT2D binding and H3K4me1/H3K27ac deposition together with decreased transcription of associated genes, indicating that H3R2me2a also exerts activation functions. Our work suggests that PRMT6 via H3R2me2a interferes with the deposition of adjacent histone marks and modulates the activity of important differentiation-associated genes by opposing transcriptional effects.