title: A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses.
abstract: BACKGROUND
  NF-κB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear.
  
  
  METHODS
  Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-κB species in Hodgkin lymphoma (HL) cells.
  
  
  RESULTS
  We found that the various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes. Yet canonical and non-canonical NF-κB dimers up- and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions. p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits. Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. These analyses also indicate that the subunit occupancy pattern of NF-κB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression. The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells.
  
  
  CONCLUSIONS
  We provide insights that are relevant for lymphomas with constitutive NF-κB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-κB signaling.
authors.affiliation: Signal Transduction in Tumor Cells, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Kivia A P
authors.initials: KA
authors.lastname: de Oliveira
authors.affiliation: Signal Transduction in Tumor Cells, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kaergel
authors.affiliation: Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany.|Genetics and Genomics of Cardiovascular Diseases, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.|Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.affiliation: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.|Present address: Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Jean-Fred
authors.initials: JF
authors.lastname: Fontaine
authors.affiliation: Genetics and Genomics of Cardiovascular Diseases, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Giannino
authors.initials: G
authors.lastname: Patone
authors.affiliation: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.|Present address: Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Muro
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany.|Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.|Present address: Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.affiliation: Genetics and Genomics of Cardiovascular Diseases, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: Signal Transduction in Tumor Cells, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany. Scheidereit@mdc-berlin.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods; D030561:Databases, Nucleic Acid; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D051550:I-kappa B Kinase
keywords: B lymphocytes; ChIP sequencing; Transcription factor; cell death; consensus sequence; enhancer; gene expression; inflammation; lymphoma; promoter