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

作者：Yang Jun; Mitra Abhishek; Dojer Norbert; Fu Shuhua; Rowicka Maga; Brasier Allan R^*

来源：Nucleic Acids Research, 2013, 41(15): 7240-7259.

DOI：10.1093/nar/gkt493

Using nuclear factor-kappa B (NF-kappa B) 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-kappa B gene network. A de novo motif enrichment analysis uncovers secondary TFBSs (AP1, SP1) at characteristic distances from NF-kappa B/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-kappa B/RelA-regulated genes and TFBSs were experimentally validated, including TANK, a negative feedback gene whose expression is NF-kappa B/RelA dependent and requires a functional interaction with the AP1 TFBSs. Our probabilistic method yields more accurate NF-kappa B/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-kappa B/RelA sub-pathways differing in biological function and temporal expression patterns.

• 出版日期2013-8