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

Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nucleic Acids Research (Impact Factor: 8.81). 04/2010; 38(7):2154-67. DOI: 10.1093/nar/gkp1180
Source: PubMed

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.

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    ABSTRACT: In eukaryotes, transcriptional regulation is usually mediated by interactions of multiple transcription factors (TFs) with their respective specific cis-regulatory elements (CREs) in the so-called cis-regulatory modules (CRMs) in DNA. Although the knowledge of CREs and CRMs in a genome is crucial to elucidate gene regulatory networks and understand many important biological phenomena, little is known about the CREs and CRMs in most eukaryotic genomes due to the difficulty to characterize them by either computational or traditional experimental methods. However, the exponentially increasing number of TF binding location data produced by the recent wide adaptation of chromatin immunoprecipitation coupled with microarray hybridization (ChIP-chip) or high-throughput sequencing (ChIP-seq) technologies has provided an unprecedented opportunity to identify CRMs and CREs in genomes. Nonetheless, how to effectively mine these large volumes of ChIP data to identify CREs and CRMs at nucleotide resolution is a highly challenging task. We have developed a novel graph-theoretic based algorithm DePCRM for genome-wide de novo predictions of CREs and CRMs using a large number of ChIP datasets. DePCRM predicts CREs and CRMs by identifying overrepresented combinatorial CRE motif patterns in multiple ChIP datasets in an effective way. When applied to 168 ChIP datasets of 56 TFs from D. melanogaster, DePCRM identified 184 and 746 overrepresented CRE motifs and their combinatorial patterns, respectively, and predicted a total of 115,932 CRMs in the genome. The predictions recover 77.9% of known CRMs in the datasets and 89.3% of known CRMs containing at least one predicted CRE. We found that the putative CRMs as well as CREs as a whole in a CRM are more conserved than randomly selected sequences. Our results suggest that the CRMs predicted by DePCRM are highly likely to be functional. Our algorithm is the first of its kind for de novo genome-wide prediction of CREs and CRMs using larger number of transcription factor ChIP datasets. The algorithm and predictions will hopefully facilitate the elucidation of gene regulatory networks in eukaryotes. All the predicted CREs, CRMs, and their target genes are available at
    BMC Genomics 12/2014; 15(1):1047. DOI:10.1186/1471-2164-15-1047 · 4.04 Impact Factor
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    ABSTRACT: Comprehensive motif discovery under experimental conditions is critical for the global understanding of gene regulation. To generate a nearly complete list of human DNA motifs under given conditions, we employed a novel approach to de novo discover significant co-occurring DNA motifs in 349 human DNase I hypersensitive site datasets. We predicted 845 to 1325 motifs in each dataset, for a total of 2684 non-redundant motifs. These 2684 motifs contained 54.02 to 75.95% of the known motifs in seven large collections including TRANSFAC. In each dataset, we also discovered 43 663 to 2 013 288 motif modules, groups of motifs with their binding sites co-occurring in a significant number of short DNA regions. Compared with known interacting transcription factors in eight resources, the predicted motif modules on average included 84.23% of known interacting motifs. We further showed new features of the predicted motifs, such as motifs enriched in proximal regions rarely overlapped with motifs enriched in distal regions, motifs enriched in 5' distal regions were often enriched in 3' distal regions, etc. Finally, we observed that the 2684 predicted motifs classified the cell or tissue types of the datasets with an accuracy of 81.29%. The resources generated in this study are available at © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
    01/2014; 43(1):gku1261. DOI:10.1093/nar/gku1261
  • 05/2013; 19(A):28. DOI:10.14806/ej.19.A.629