Kolovos, Petros ORCID: 0000-0002-0787-6158, Georgomanolis, Theodore, Koeferle, Anna, Larkin, Joshua D., Brant, Lilija, Nikolic, Milos ORCID: 0000-0003-0029-7601, Gusmao, Eduardo G., Zirkel, Anne, Knoch, Tobias A., van Ijcken, Wilfred F., Cook, Peter R., Costa, Ivan G. ORCID: 0000-0003-2890-8697, Grosveld, Frank G. and Papantonis, Argyris ORCID: 0000-0001-7551-1073 (2016). Binding of nuclear factor kappa B to noncanonical consensus sites reveals its multimodal role during the early inflammatory response. Genome Res., 26 (11). S. 1478 - 1490. COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 1549-5469

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kolovos, PetrosUNSPECIFIEDorcid.org/0000-0002-0787-6158UNSPECIFIED
Georgomanolis, TheodoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeferle, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larkin, Joshua D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brant, LilijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikolic, MilosUNSPECIFIEDorcid.org/0000-0003-0029-7601UNSPECIFIED
Gusmao, Eduardo G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zirkel, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoch, Tobias A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Ijcken, Wilfred F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cook, Peter R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costa, Ivan G.UNSPECIFIEDorcid.org/0000-0003-2890-8697UNSPECIFIED
Grosveld, Frank G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDorcid.org/0000-0001-7551-1073UNSPECIFIED
URN: urn:nbn:de:hbz:38-257287
DOI: 10.1101/gr.210005.116
Journal or Publication Title: Genome Res.
Volume: 26
Number: 11
Page Range: S. 1478 - 1490
Date: 2016
Publisher: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication: COLD SPRING HARBOR
ISSN: 1549-5469
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHROMOSOME CONFORMATION CAPTURE; GENERATION SEQUENCING DATA; RNA-SEQ DATA; GLUCOCORTICOID-RECEPTOR; SUPER-ENHANCER; TRANSCRIPTION FACTORIES; GENOMIC INTERACTIONS; CELL IDENTITY; GENES; CHROMATINMultiple languages
Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25728

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