On the detection and refinement of transcription factor binding sites using ChIP-Seq data

Nucleic Acids Res. 2010 Apr;38(7):2154-67. doi: 10.1093/nar/gkp1180. Epub 2010 Jan 6.

Abstract

Coupling chromatin immunoprecipitation (ChIP) with recently developed massively parallel sequencing technologies has enabled genome-wide detection of protein-DNA interactions with unprecedented sensitivity and specificity. This new technology, ChIP-Seq, presents opportunities for in-depth analysis of transcription regulation. In this study, we explore the value of using ChIP-Seq data to better detect and refine transcription factor binding sites (TFBS). We introduce a novel computational algorithm named Hybrid Motif Sampler (HMS), specifically designed for TFBS motif discovery in ChIP-Seq data. We propose a Bayesian model that incorporates sequencing depth information to aid motif identification. Our model also allows intra-motif dependency to describe more accurately the underlying motif pattern. Our algorithm combines stochastic sampling and deterministic 'greedy' search steps into a novel hybrid iterative scheme. This combination accelerates the computation process. Simulation studies demonstrate favorable performance of HMS compared to other existing methods. When applying HMS to real ChIP-Seq datasets, we find that (i) the accuracy of existing TFBS motif patterns can be significantly improved; and (ii) there is significant intra-motif dependency inside all the TFBS motifs we tested; modeling these dependencies further improves the accuracy of these TFBS motif patterns. These findings may offer new biological insights into the mechanisms of transcription factor regulation.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms*
  • Amino Acid Motifs
  • Bayes Theorem
  • Binding Sites
  • Chromatin Immunoprecipitation / methods*
  • Computational Biology
  • Computer Simulation
  • Sequence Analysis, DNA*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors