19th-banner-rev.gif

Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

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 CpG dinucleotides is enhanced at least eight-fold 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.

References

    Fox KR (1986) The effect of HhaI methylation on DNA local structure. Biochem J 234(1):213-216.

    Suck D (1994) DNA recognition by DNase I. J Mol Recognit 7(2):65-70. Rohs R, et al. (2009) The role of DNA shape in protein-DNA recognition. Nature 461(7268):1248-1253


Allan Lazarovici1,2
Tianyin Zhou3
Anthony Shafer4
Ana Carolina Dantas Machado 3
Richard Sandstrom4
Peter J. Sabo 4
Yan Lu3
Remo Rohs3
John A. Stamatoyannopoulos4
Harmen J. Bussemaker2,5

1Department of Electrical Engineering
Columbia University
New York, NY 10027
2 Department of Biological Sciences
Columbia University
New York, NY 10027
3 Departments of Biological Sciences, Chemistry, and Physics and Astronomy
University of Southern California
Los Angeles, CA 90089
4 Departments of Genome Sciences and Medicine
University of Washington
Seattle, WA 98195
5 Center for Computational Biology and Bioinformatics
Columbia University,
New York, NY 10032

Phone: (212) 854-9932
Fax: (212) 854-1527
hjb2004@columbia.edu