The NF-κB Genomic Landscape in Lymphoblastoid B Cells
Author(s)Zhao, Bo; Barrera, Luis A.; Ersing, Ina; Willox, Bradford; Greenfeld, Hannah; Zhou, Hufeng; Mollo, Sarah B.; Shi, Tommy T.; Takasaki, Kaoru; Jiang, Sizun; Cahir-McFarland, Ellen; Kellis, Manolis; Bulyk, Martha L.; Kieff, Elliott; Gewurz, Benjamin E.; Schmidt, Stefanie C. S.; Barrera, Luis A.; ... Show more Show less
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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.
DepartmentHarvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Zhao, Bo, Luis A. Barrera, Ina Ersing, Bradford Willox, Stefanie C.S. Schmidt, Hannah Greenfeld, Hufeng Zhou, et al. “The NF-κB Genomic Landscape in Lymphoblastoid B Cells.” Cell Reports 8, no. 5 (September 2014): 1595–1606.
Final published version