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Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088591/ https://www.ncbi.nlm.nih.gov/pubmed/27633323 http://dx.doi.org/10.1101/gr.210005.116 |
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author | Kolovos, Petros Georgomanolis, Theodore Koeferle, Anna Larkin, Joshua D. Brant, Lilija Nikolicć, Miloš Gusmao, Eduardo G. Zirkel, Anne Knoch, Tobias A. van Ijcken, Wilfred F. Cook, Peter R. Costa, Ivan G. Grosveld, Frank G. Papantonis, Argyris |
author_facet | Kolovos, Petros Georgomanolis, Theodore Koeferle, Anna Larkin, Joshua D. Brant, Lilija Nikolicć, Miloš Gusmao, Eduardo G. Zirkel, Anne Knoch, Tobias A. van Ijcken, Wilfred F. Cook, Peter R. Costa, Ivan G. Grosveld, Frank G. Papantonis, Argyris |
author_sort | Kolovos, Petros |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5088591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50885912017-05-01 Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response Kolovos, Petros Georgomanolis, Theodore Koeferle, Anna Larkin, Joshua D. Brant, Lilija Nikolicć, Miloš Gusmao, Eduardo G. Zirkel, Anne Knoch, Tobias A. van Ijcken, Wilfred F. Cook, Peter R. Costa, Ivan G. Grosveld, Frank G. Papantonis, Argyris Genome Res Research 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. Cold Spring Harbor Laboratory Press 2016-11 /pmc/articles/PMC5088591/ /pubmed/27633323 http://dx.doi.org/10.1101/gr.210005.116 Text en © 2016 Kolovos et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Kolovos, Petros Georgomanolis, Theodore Koeferle, Anna Larkin, Joshua D. Brant, Lilija Nikolicć, Miloš Gusmao, Eduardo G. Zirkel, Anne Knoch, Tobias A. van Ijcken, Wilfred F. Cook, Peter R. Costa, Ivan G. Grosveld, Frank G. Papantonis, Argyris Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title | Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title_full | Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title_fullStr | Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title_full_unstemmed | Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title_short | Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
title_sort | binding of nuclear factor κb to noncanonical consensus sites reveals its multimodal role during the early inflammatory response |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088591/ https://www.ncbi.nlm.nih.gov/pubmed/27633323 http://dx.doi.org/10.1101/gr.210005.116 |
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