103 Probing DNA shape and methylation state on a genomic scale with DNase I |
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| Authors: | Allan Lazarovici Tianyin Zhou Anthony Shafer Ana Carolina Dantas Machado Richard Sandstrom Peter J Sabo |
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| Institution: | 1. Department of Electrical Engineering , Columbia University , New York , NY , 10027 , USA;2. Department of Biological Sciences , Columbia University , New York , NY , 10027 , USA;3. Molecular and Computational Biology Program, Departments of Biological Sciences, Chemistry, and Physics and Astronomy , University of Southern California , Los Angeles , CA , 90089 , USA;4. Departments of Genome Sciences and Medicine , University of Washington , Seattle , WA , 98195 , USA |
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| Abstract: | 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 genome reveals that the cleavage directly adjacent to CpG dinucleotides is enhanced at least eight-fold by cytosine methylation. This phenomenon we show is 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 through which CpG methylation can modulate protein–DNA interaction strength via the remodeling of DNA shape. |
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