Detecting clustering and ordering binding patterns among transcription factors via point process models

Abstract

Motivation: Recent development in ChIP-Seq technology has generated binding data for many transcription factors (TFs) in various cell types and cellular conditions. This opens great opportunities for studying combinatorial binding patterns among a set of TFs active in a particular cellular condition, which is a key component for understanding the interaction between TFs in gene regulation. Results: As a first step to the identification of combinatorial binding patterns, we develop statistical methods to detect clustering and ordering patterns among binding sites (BSs) of a pair of TFs. Testing procedures based on Ripley's K-function and its generalizations are developed to identify binding patterns from large collections of BSs in ChIP-Seq data. We have applied our methods to the ChIP-Seq data of 91 pairs of TFs in mouse embryonic stem cells. Our methods have detected clustering binding patterns between most TF pairs, which is consistent with the findings in the literature, and have identified significant ordering preferences, relative to the direction of target gene transcription, among the BSs of seven TFs. More interestingly, our results demonstrate that the identified clustering and ordering binding patterns between TFs are associated with the expression of the target genes. These findings provide new insights into co-regulation between TFs. © The Author 2014.