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Bioinformatics Advance Access originally published online on December 6, 2005
Bioinformatics 2006 22(4):423-429; doi:10.1093/bioinformatics/bti815
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A hypothesis-based approach for identifying the binding specificity of regulatory proteins from chromatin immunoprecipitation data

Kenzie D. MacIsaac 1, D. Benjamin Gordon 2, Lena Nekludova 2, Duncan T. Odom 2, Joerg Schreiber 2, David K. Gifford 1, Richard A. Young 2,3 and Ernest Fraenkel 1,2,4,*

1MIT Computer Science and Artificial Intelligence Laboratory 32 Vassar Street, Cambridge, MA 02139, USA
2Whitehead Institute for Biomedical Research, Nine Cambridge Center Cambridge, MA 02142, USA
3Department of Biology, Massachusetts Institute of Technology Cambridge, MA 02139, USA
4Division of Biological Engineering, Massachusetts Institute of Technology Cambridge, MA 02139, USA

*To whom correspondence should be addressed.

Motivation: Genome-wide chromatin-immunoprecipitation (ChIP-chip) detects binding of transcriptional regulators to DNA in vivo at low resolution. Motif discovery algorithms can be used to discover sequence patterns in the bound regions that may be recognized by the immunoprecipitated protein. However, the discovered motifs often do not agree with the binding specificity of the protein, when it is known.

Results: We present a powerful approach to analyzing ChIP-chip data, called THEME, that tests hypotheses concerning the sequence specificity of a protein. Hypotheses are refined using constrained local optimization. Cross-validation provides a principled standard for selecting the optimal weighting of the hypothesis and the ChIP-chip data and for choosing the best refined hypothesis. We demonstrate how to derive hypotheses for proteins from 36 domain families. Using THEME together with these hypotheses, we analyze ChIP-chip datasets for 14 human and mouse proteins. In all the cases the identified motifs are consistent with the published data with regard to the binding specificity of the proteins.

Availability: THEME is freely available for download.

Contact: fraenkel-admin{at}mit.edu

Supplementary information: http://fraenkel.mit.edu/THEME

Received on September 14, 2005; revised on November 14, 2005; accepted on December 1, 2005

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