Cell Reports
Volume 8, Issue 5, 11 September 2014, Pages 1595-1606
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The NF-κB Genomic Landscape in Lymphoblastoid B Cells

https://doi.org/10.1016/j.celrep.2014.07.037Get rights and content
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Highlights

  • A complex NF-κB genomic landscape results from activation of both NF-κB pathways

  • Ten promoter and 11 enhancer NF-κB subunit-binding patterns are observed

  • One-third of NF-κB sites lack a κB motif and are enriched for other motifs

  • FOXM1 is recruited to half of κB sites and forms a complex with NF-κB on DNA

Summary

The nuclear factor κB (NF-κΒ) subunits RelA, RelB, cRel, p50, and p52 are each critical for B cell development and function. To systematically characterize their responses to canonical and noncanonical NF-κB pathway activity, we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) analysis in lymphoblastoid B cell lines (LCLs). We found a complex NF-κB-binding landscape, which did not readily reflect the two NF-κB pathway paradigms. Instead, 10 subunit-binding patterns were observed at promoters and 11 at enhancers. Nearly one-third of NF-κB-binding sites lacked κB motifs and were instead enriched for alternative motifs. The oncogenic forkhead box protein FOXM1 co-occupied nearly half of NF-κB-binding sites and was identified in protein complexes with NF-κB on DNA. FOXM1 knockdown decreased NF-κB target gene expression and ultimately induced apoptosis, highlighting FOXM1 as a synthetic lethal target in B cell malignancy. These studies provide a resource for understanding mechanisms that underlie NF-κB nuclear activity and highlight opportunities for selective NF-κB blockade.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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