Learning the human chromatin network from all ENCODE ChIP-seq data

Introduction: A cell's epigenome arises from interactions among regulatory factors --- transcription factors, histone modifications, and other DNA-associated proteins --- co-localized at particular genomic regions. Identifying the network of interactions among regulatory factors, the chromatin network, is of paramount importance in understanding epigenome regulation. Methods: We developed a novel computational approach, ChromNet, to infer the chromatin network from a set of ChIP-seq datasets. ChromNet has four key features that enable its use on large collections of ChIP-seq data. First, rather than using pairwise co-localization of factors along the genome, ChromNet identifies conditional dependence relationships that better discriminate direct and indirect interactions. Second, our novel statistical technique, the group graphical model, improves inference of conditional dependence on highly correlated datasets. Such datasets are common because some transcription factors form a complex and the same transcription factor is often assayed in different laboratories or cell types. Third, ChromNet's computationally efficient method and the group graphical model enable the learning of a joint network across all cell types, which greatly increases the scope of possible interactions. We have shown that this results in a significantly higher fold enrichment for validated protein interactions. Fourth, ChromNet provides an efficient way to identify the genomic context that drives a particular network edge, which provides a more comprehensive understanding of regulatory factor interactions. Results: We applied ChromNet to all available ChIP-seq data from the ENCODE Project, consisting of 1451 ChIP-seq datasets, which revealed previously known physical interactions better than alternative approaches. ChromNet also identified previously unreported regulatory factor interactions. We experimentally validated one of these interactions, between the MYC and HCFC1 transcription factors. Discussion: ChromNet provides a useful tool for understanding the interactions among regulatory factors and identifying novel interactions. We have provided an interactive web-based visualization of the full ENCODE chromatin network and the ability to incorporate custom datasets at http://chromnet.cs.washington.edu.

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