A probabilistic approach to learn chromatin architecture and accurate inference of the NF- B/RelA regulatory network using ChIP-Seq

Department of Internal Medicine, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1060, USA, Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1060, USA, Institute for Translational Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1060, USA, Institute of Informatics, University of Warsaw, Banacha 2, 02-097, Warsaw, Poland and Sealy Center for Molecular Medicine, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1060, USA.
Nucleic Acids Research (Impact Factor: 9.11). 06/2013; 41(15). DOI: 10.1093/nar/gkt493
Source: PubMed


Using nuclear factor-κB (NF-κB) ChIP-Seq data, we present a framework for iterative learning of regulatory networks. For every possible transcription factor-binding site (TFBS)-putatively regulated gene pair, the relative distance and orientation are calculated to learn which TFBSs are most likely to regulate a given gene. Weighted TFBS contributions to putative gene regulation are integrated to derive an NF-κB gene network. A de novo motif enrichment analysis uncovers secondary TFBSs (AP1, SP1) at characteristic distances from NF-κB/RelA TFBSs. Comparison with experimental ENCODE ChIP-Seq data indicates that experimental TFBSs highly correlate with predicted sites. We observe that RelA-SP1-enriched promoters have distinct expression profiles from that of RelA-AP1 and are enriched in introns, CpG islands and DNase accessible sites. Sixteen novel NF-κB/RelA-regulated genes and TFBSs were experimentally validated, including TANK, a negative feedback gene whose expression is NF-κB/RelA dependent and requires a functional interaction with the AP1 TFBSs. Our probabilistic method yields more accurate NF-κB/RelA-regulated networks than a traditional, distance-based approach, confirmed by both analysis of gene expression and increased informativity of Genome Ontology annotations. Our analysis provides new insights into how co-occurring TFBSs and local chromatin context orchestrate activation of NF-κB/RelA sub-pathways differing in biological function and temporal expression patterns.

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