Abstract
BackgroundNF-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.MethodsUsing 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.ResultsWe 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.ConclusionsWe 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 materialThe online version of this article (doi:10.1186/s13073-016-0280-5) contains supplementary material, which is available to authorized users.
Highlights
nuclear factor κB (NF-κB) is widely involved in lymphoid malignancies; the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear
Our results revealed that NF-κB-inducing kinase (NIK) promotes the formation of both p50 and p52, which account for most NF-κB activity in Hodgkin lymphoma (HL) cells
Predominance of p50 and p52 and non-canonical inhibitor of κB (IκB) kinase (IKK) signaling in the constitutive NF-κB activity in HL To test the relative contribution of canonical and noncanonical NF-κB dimers in HL cells, we depleted NIK, a central component of non-canonical NF-κB signaling
Summary
NF-κB is widely involved in lymphoid malignancies; the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear. The NF-κB family of transcription factors (TFs) includes RelA (p65), RelB, c-Rel, and the precursor proteins p105 and p100, which are processed to p50 and p52, respectively. These subunits can form various homo- and heterodimers which regulate gene expression by binding to κB sites in the promoters and enhancers of genes in a wide range of mammalian cell types. NF-κB activation can be achieved through the canonical and noncanonical signaling pathways. The non-canonical pathway depends on the activation of NF-κB-inducing kinase (NIK) and IκB kinase α (IKKα), resulting in the induction of NF-κB dimers containing p52 and/or RelB [1,2,3]. Stimulation through LTβR results in the parallel production of p50 and p52, and both are important to assure the full range of signalinduced gene expression [4]
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