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Relative Avidity, Specificity, and Sensitivity of Transcription Factor–DNA Binding in Genome-Scale Experiments

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Protein Networks and Pathway Analysis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 563))

Abstract

One of the most crucial problems with genome-wide experimental analysis is how to extract meaningful biological phenomena from the resulting large data sets. Here, we present modeling and prediction techniques that are applied to genome-wide identification of in vivo protein–DNA binding sites from ChIP-based data sets. We develop a simple mixture probabilistic model of occurrence of non-specific and specific TF–DNA binding events for transcription factor binding to any site in the genome. We calculated the statistical significance of specific and non-specific random binding events using Kolmogorov–Waring and exponential functions, respectively. The binding events in the chromosome regions associated with non-specific, non-random binding loci were also identified and filtered out. The mixture model fits equally well to five different TFs (ERE, CREB, STAT1, Nanog, Oct4) data provided by ChIP-PET, SACO, and ChIP-Seq methods included in this study. We present a uniform methodology for estimating specificity, total number of binding sites, and sensitivity of data sets detected by these ChIP-based genome-wide experimental systems. We demonstrate strong heterogeneity of specific TF–DNA binding sites in terms of their avidity and by correlation between observed relative binding avidity of specific TF–DNA binding site and the level of mRNA transcription of the nearest gene target. Finally, we conclude that the sensitivity problem has not been resolved by current ChIP-based methods, including ChIP-Seq.

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Acknowledgments

I thank Chia Lin Wei, Chiu Kow Ping, and Ruan Yujin for providing access to ChIP-Seq data sets of T2G DB and for very useful discussions of their ChIP-PET method. I also thank Piroon Jenjaroenpoon, Yuri Orlov, and Onkar Singh for partial but important computational support of analytical part of this work. I express my special acknowledgment to Yuri Nikolsky for his stimulated interest in this study. This work was supported by BII/A-Star, Singapore.

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  1. Bioinformatics Institute, Biopolis, A-STAR, Singapore

    Vladimir A. Kuznetsov

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  1. Vladimir A. Kuznetsov
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Editors and Affiliations

  1. GeneGo Inc., Saxony Road 169, Encinitas, 92024, U.S.A.

    Yuri Nikolsky

  2. GeneGo Inc., Saxony Road 169, Encinitas, 92024, U.S.A.

    Julie Bryant

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC

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Kuznetsov, V.A. (2009). Relative Avidity, Specificity, and Sensitivity of Transcription Factor–DNA Binding in Genome-Scale Experiments. In: Nikolsky, Y., Bryant, J. (eds) Protein Networks and Pathway Analysis. Methods in Molecular Biology, vol 563. Humana Press. https://doi.org/10.1007/978-1-60761-175-2_2

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  • DOI: https://doi.org/10.1007/978-1-60761-175-2_2

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  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-174-5

  • Online ISBN: 978-1-60761-175-2

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