A novel mechanism implicates the transcription factor NF-κB in gene repression during acute proinflammatory signaling

This finding offers novel putative targets for manipulating the way by which extra-cellular signaling unfolds in human cells which may open new perspective for the development of therapeutic approaches for the treatment of inflammatory diseases.

The key activator of the proinflammatory response has now been shown to also directly invoke gene repression via association with non-canonical binding sites in human cells. The study, just published in Genome Research, was led by the group of Dr. Argyris Papantonis at the Center for Molecular Medicine in collaboration with groups from the Universities of Oxford (UK), Aachen (DE), and the Erasmus Medical Center (NL).

NF-κB is the transcription factor responsible for the activation of proinflammatory genes during the acute phase that follows stimulation of human endothelial cells with the cytokine tumour necrosis factor alpha (TNF). There exist >500,000 cognate binding sites for NF-κB in the human genome, but the factor only binds ~8,000 of them; the mechanism underlying this selectivity are poorly understood. Even more surprisingly, the work by Argyris Papantonis and colleagues revealed that more than half of these sites do not contain the expected, canonical, recognition motif for NF-κΒ.

Using a combination of cutting-edge genome-wide approaches, computational analyses, and precision genome editing the authors were able to show that NF-κB binding to these “non-canonical” sites in the genome correlates with an unforeseen repressive function of the transcription factor. This highlights how in every signaling cascade it is as important to “switch off” active genes, as it is to “switch on” inactive ones – and such a bimodal mode of action is bound to be a universal feature of many different signaling cascades. This finding offers novel putative targets for manipulating the way by which extra-cellular signaling unfolds in human cells.

These results have been accepted for publication in the prestigious journal: Genome Research, from Cold Spring Harbor Press, and will feature in the upcoming issue:

Petros Kolovos, Theodore Georgomanolis, Anna Koeferle, Joshua D. Larkin, Lilija Brant, Miloš Nikolić, Eduardo G. Gusmao, Anne Zirkel, Tobias A. Knoch, Wilfred F. van Ijcken, Peter R. Cook, Ivan G. Costa, Frank G. Grosveld, and Argyris Papantonis.

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response. Genome Res. Published in Advance September 15, 2016, doi:10.1101/gr.210005.116.

For further information, please visit also:
http://www.cmmc-uni-koeln.de/research/research-areas-projects/research-area-b-principles-of-immunity-inflammation-and-infection/papantonis-a-jrg-viii/

or contact:

Dr. rer. nat. Argyris Papantonis

Center for Molecular Medicine Cologne

CMMC Research Building
Robert-Koch-Str. 21
50931 Cologne