Probing DNA shape and methylation state on a genomic scale with DNase I

DNA binding proteins find their cognate sequences within genomic DNA through recognition of specific chemical and structural features. Here we demonstrate that high-resolution DNase I cleavage profiles can provide detailed information about the shape and chemical modification status of genomic DNA. Analyzing millions of DNA backbone hydrolysis events on naked genomic DNA, we show that the intrinsic rate of cleavage by DNase I closely tracks the width of the minor groove. Integration of these DNase I cleavage data with bisulfite sequencing data for the same cell type’s genome reveals that cleavage directly adjacent to cytosine-phosphate-guanine (CpG) dinucleotides is enhanced at least eightfold by cytosine methylation. This phenomenon we show to be attributable to methylation-induced narrowing of the minor groove. Furthermore, we demonstrate that it enables simultaneous mapping of DNase I hypersensitivity and regional DNA methylation levels using dense in vivo cleavage data. Taken together, our results suggest a general mechanism by which CpG methylation can modulate protein–DNA interaction strength via the remodeling of DNA shape.