title: The NF-κB genomic landscape in lymphoblastoid B cells.
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.
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Barrera
authors.affiliation: 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.
authors.forename: Ina
authors.initials: I
authors.lastname: Ersing
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Bradford
authors.initials: B
authors.lastname: Willox
authors.affiliation: 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.
authors.forename: Stefanie C S
authors.initials: SC
authors.lastname: Schmidt
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Greenfeld
authors.affiliation: 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.
authors.forename: Hufeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Mollo
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Tommy T
authors.initials: TT
authors.lastname: Shi
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takasaki
authors.affiliation: 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.
authors.forename: Sizun
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Cahir-McFarland
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: 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.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Bulyk
authors.affiliation: 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.
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
authors.affiliation: 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.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Gewurz
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D021122:Protein Subunits