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

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.