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An algorithm for finding protein–DNA binding sites with applications to chromatin- immunoprecipitation microarray experiments

Nature Biotechnology volume 20, pages 835–839 (2002)Cite this article

Abstract

Chromatin immunoprecipitation followed by cDNA microarray hybridization (ChIP–array) has become a popular procedure for studying genome-wide protein–DNA interactions and transcription regulation. However, it can only map the probable protein–DNA interaction loci within 1–2 kilobases resolution. To pinpoint interaction sites down to the base-pair level, we introduce a computational method, Motif Discovery scan (MDscan), that examines the ChIP–array-selected sequences and searches for DNA sequence motifs representing the protein–DNA interaction sites. MDscan combines the advantages of two widely adopted motif search strategies, word enumeration1,2,3,4 and position-specific weight matrix updating5,6,7,8,9, and incorporates the ChIP–array ranking information to accelerate searches and enhance their success rates. MDscan correctly identified all the experimentally verified motifs from published ChIP–array experiments in yeast10,11,12,13 (STE12, GAL4, RAP1, SCB, MCB, MCM1, SFF, and SWI5), and predicted two motif patterns for the differential binding of Rap1 protein in telomere regions. In our studies, the method was faster and more accurate than several established motif-finding algorithms5,8,9. MDscan can be used to find DNA motifs not only in ChIP–array experiments but also in other experiments in which a subgroup of the sequences can be inferred to contain relatively abundant motif sites. The MDscan web server can be accessed at http://BioProspector.stanford.edu/MDscan/.

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Acknowledgements

The authors thank the Brown lab at Stanford (especially Jason D. Lieb) and the Young lab at MIT (especially Bing Ren) for their valuable data and scientific insight. This work is supported by National Human Genome Research Institute grants R01 HGF02235 and R01 HG02518-01, and National Science Foundation grant DMS-0094613.

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Authors and Affiliations

  1. Stanford Medical Informatics, Stanford University, Stanford, 94305, CA

    X. Shirley Liu

  2. Department of Biochemistry, Stanford University, Stanford, 94305, CA

    Douglas L. Brutlag

  3. Department of Statistics, Harvard University, 1 Oxford Street, Cambridge, 02138, MA

    Jun S. Liu

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  1. X. Shirley Liu
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  2. Douglas L. Brutlag
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  3. Jun S. Liu
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Correspondence to Jun S. Liu.

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Liu, X., Brutlag, D. & Liu, J. An algorithm for finding protein–DNA binding sites with applications to chromatin- immunoprecipitation microarray experiments. Nat Biotechnol 20, 835–839 (2002). https://doi.org/10.1038/nbt717

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