Binding of nuclear factor kappa B to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

Petros Kolovos, T Georgomanolis, A Koeferle, JD Larkin, L Brant, M Nikolic, EG Gusmao, A Zirkel, Tobias Knoch, Wilfred van Ijcken, PR Cook, IG Costa, Frank Grosveld, A Papantonis

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)

Abstract

Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-kappa B, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-kappa B binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-kappa B-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-kappa B and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-kappa B that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression.
Original languageUndefined/Unknown
Pages (from-to)1478-1489
Number of pages12
JournalGenome Research
Volume26
Issue number11
DOIs
Publication statusPublished - 2016

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