1. A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses
- Author
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de Oliveira, K.A., Kaergel, E., Heinig, M., Fontaine, J.F., Patone, G., Muro, E.M., Mathas, S., Hummel, M., Andrade-Navarro, M.A., Hubner, N., and Scheidereit, C.
- Subjects
Transcriptional Activation ,Chromatin Immunoprecipitation ,Cell Survival ,lymphoma ,NF-kappa B p52 Subunit ,Cell Line, Tumor ,ChIP sequencing ,Humans ,Nucleotide Motifs ,Binding Sites ,promoter ,Research ,Transcription Factor RelB ,NF-kappa B ,Transcription Factor RelA ,Computational Biology ,High-Throughput Nucleotide Sequencing ,NF-kappa B p50 Subunit ,Hodgkin Disease ,I-kappa B Kinase ,Gene Expression Regulation, Neoplastic ,cell death ,consensus sequence ,inflammation ,gene expression ,B Lymphocytes ,Chip Sequencing ,Transcription Factor ,Cell Death ,Consensus Sequence ,Enhancer ,Gene Expression ,Inflammation ,Lymphoma ,Promoter ,enhancer ,Protein Multimerization ,Transcription factor ,Databases, Nucleic Acid ,Genome-Wide Association Study ,Protein Binding ,Signal Transduction ,B lymphocytes - 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. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0280-5) contains supplementary material, which is available to authorized users.
- Published
- 2015