Abstract
DNA-methylation is a key epigenetic mark in chromatin that attenuates chromatin accessibility during transcription, implying a crucial role in gene regulation. Its symmetrical distribution and function is thought to be linked to the periodicity of the DNA helix and the positioning of DNA wrapped around the nucleosome. Epigenomic data suggest that DNA methyltransferases (DNMTs) can methylate DNA when wrapped around a histone octamer. Yet, how this is precisely linked to positioning and periodicity is yet to be elucidated. It has been hypothesized that the observed methylation patterns may be related to the changing accessibility of nucleosome-bound DNA to DNMTs. Here, incorporating NOMe-Seq data, which simultaneously measures nucleosome positioning and DNA methylation at CpG sites across the genome, the interaction of DNMT1 with nucleosomal DNA could be mechanistically modeled and compared to hypothesized dependencies. Furthermore, X-ray structures of DNMT1 were superimposed onto those of nucleosome core complexes at base resolution to determine which histone-bound DNA positions would be sterically accessible or inaccessible to DNMTs. Statistical comparison with experimental NOMe-Seq data revealed that structurally computed DNA accessibility scores can indeed explain DNA methylation patterns in actively transcribed regions with positioned high nucleosome density.