New publication in "Communications Biology"

Cellular DNA is wrapped on nucleosomes, but how DNA methylation occurs on nucleosomal DNA is not known. In this study, we investigated DNA methylation of unmodified, as well as H3K4me3 and H3K36me3 containing mononucleosomes by the DNMT3A DNA methyltransferase. We observed protection of nucleosomal DNA against methylation, but efficient methylation of the linker DNA indicating that for complete DNA methylation cooperation with chromatin remodeling activity will be necessary. We show that H3K4me3 reduced methylation close to the nucleosome, while H3K _C36me3 has a stimulatory effect on the methylation of the linker DNA. Strikingly, the stimulation by H3K36me3 was independent of the PWWP domain of DNMT3A revealing novel role of H3K36me3 in directly stimulating linker DNA methylation by DNMT3A. Further studies suggest K36 methylation hinders the interaction of the H3-tail with the linker DNA and thereby provides better access for DNMT3A to the DNA. Based on this we propose an evolutionary model, in which the direct stimulation of DNA methylation by H3K36me3 preceded its PWWP domain mediated signaling effect.