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Cell Rep. 2014 Sep 11;8(5):1595-606. doi: 10.1016/j.celrep.2014.07.037. Epub 2014 Aug 21.

The NF-κB genomic landscape in lymphoblastoid B cells.

Author information

1
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
4
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: mlbulyk@receptor.med.harvard.edu.
6
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bgewurz@partners.org.

Abstract

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.

PMID:
25159142
PMCID:
PMC4163118
DOI:
10.1016/j.celrep.2014.07.037
[Indexed for MEDLINE]
Free PMC Article

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