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Probing DNA shape and methylation state on a genomic scale with DNase I
Open accessAbstract
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.
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“Adding a methyl group to the cytosine could affect the local DNA shape, as evidenced by the altered DNase I digestion rate and patterns70,71.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [71]
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Metadata
- Authors
- Lazarovici, A., Zhou, T., Shafer, A., Dantas Machado, A. C., Riley, T. R., Sandstrom, R., Sabo, P. J., Lu, Y., Rohs, R., Stamatoyannopoulos, J. A., & Bussemaker, H. J.
- Affiliations
- Columbia University (US)
- University of Southern California (US)
- University of Washington (US)
- Molecular and Computational Biology Program, Departments of Biological Sciences, Chemistry, Physics and Astronomy, and Computer Science, University of Southern California, Los Angeles, CA 90089;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04
- Volume
- 110
- Issue
- 16
- Pages
- 6376-6381
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3631675
- OpenAlex
- W1984521378
- Cited by
- 162
- References
- 47
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 9 · 2023: 4 · 2022: 14 · 2021: 15 · 2020: 11 · 2019: 19 · 2018: 12 · 2017: 17 · 2016: 13 · 2015: 19 · 2014: 12 · 2013: 6
- FWCI
- 7.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Human Genome Research Institute (U54HG004592, R01HG003008)
- National Cancer Institute (U54CA121852)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- DNase I cleavage, DNA methylation, CpG, DNA shape, DNase I hypersensitivity, bisulfite sequencing, protein-DNA interactions
- MeSH terms
- Cells, Cultured, Deoxyribonuclease I, DNA, Humans, Models, Genetic, Models, Molecular, Nucleic Acid Conformation, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Genomics
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