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Genome Res. 2016 Nov;26(11):1478-1489. Epub 2016 Sep 15.

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

Author information

1
Department of Cell Biology, Erasmus Medical Centre, 3015 CN Rotterdam, The Netherlands.
2
Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany.
3
Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom.
4
IZKF Computational Biology Research Group, RWTH Aachen University Medical School, 52062 Aachen, Germany.
5
Center for Biomics, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.

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-κB, 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-κB binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-κΒ-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-κΒ 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-κΒ 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.

PMID:
27633323
PMCID:
PMC5088591
DOI:
10.1101/gr.210005.116
[Indexed for MEDLINE]
Free PMC Article

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