Universität zu Köln

Weiterer, Sinah-Sophia, Meier-Soelch, Johanna, Georgomanolis, Theodore, Mizi, Athanasia ORCID: 0000-0002-4313-491X, Beyerlein, Anna, Weiser, Hendrik, Brant, Lilija, Mayr-Buro, Christin, Jurida, Liane, Beuerlein, Knut, Mueller, Helmut, Weber, Axel, Tenekeci, Ulas, Dittrich-Breiholz, Oliver, Bartkuhn, Marek, Nist, Andrea, Stiewe, Thorsten ORCID: 0000-0003-0134-7826, van IJcken, Wilfred F. J., Riedlinger, Tabea, Schmitz, M. Lienhard ORCID: 0000-0002-6984-7192, Papantonis, Argyris ORCID: 0000-0001-7551-1073 and Kracht, Michael (2020). Distinct IL-1 alpha-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. Embo J., 39 (1). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

How cytokine-driven changes in chromatin topology are converted into gene regulatory circuits during inflammation still remains unclear. Here, we show that interleukin (IL)-1 alpha induces acute and widespread changes in chromatin accessibility via the TAK1 kinase and NF-kappa B at regions that are highly enriched for inflammatory disease-relevant SNPs. Two enhancers in the extended chemokine locus on human chromosome 4 regulate the IL-1 alpha-inducible IL8 and CXCL1-3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL-1 alpha/TAK1-inducible manner. Microdeletions of p65-binding sites in either of the two enhancers impair NF-kappa B recruitment, suppress activation and biallelic transcription of the IL8/CXCL2 genes, and reshuffle higher-order chromatin interactions as judged by i4C interactome profiles. Notably, these findings support a dominant role of the IL8 master enhancer in the regulation of sustained IL-1 alpha signaling, as well as for IL-8 and IL-6 secretion. CRISPR-guided transactivation of the IL8 locus or cross-TAD regulation by TNF alpha-responsive enhancers in a different model locus supports the existence of complex enhancer hierarchies in response to cytokine stimulation that prime and orchestrate proinflammatory chromatin responses downstream of NF-kappa B.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weiterer, Sinah-Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Meier-Soelch, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Georgomanolis, Theodore UNSPECIFIED UNSPECIFIED UNSPECIFIED Mizi, Athanasia UNSPECIFIED orcid.org/0000-0002-4313-491X UNSPECIFIED Beyerlein, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiser, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Brant, Lilija UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr-Buro, Christin UNSPECIFIED UNSPECIFIED UNSPECIFIED Jurida, Liane UNSPECIFIED UNSPECIFIED UNSPECIFIED Beuerlein, Knut UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Helmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Tenekeci, Ulas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dittrich-Breiholz, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartkuhn, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Nist, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Stiewe, Thorsten UNSPECIFIED orcid.org/0000-0003-0134-7826 UNSPECIFIED van IJcken, Wilfred F. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedlinger, Tabea UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz, M. Lienhard UNSPECIFIED orcid.org/0000-0002-6984-7192 UNSPECIFIED Papantonis, Argyris UNSPECIFIED orcid.org/0000-0001-7551-1073 UNSPECIFIED Kracht, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-128061
DOI:	10.15252/embj.2019101533
Journal or Publication Title:	Embo J.
Volume:	39
Number:	1
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1460-2075
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; PROTEIN-KINASE; 3-DIMENSIONAL ORGANIZATION; TRANSCRIPTION; EXPRESSION; INTERLEUKIN-1; ACTIVATION; HELA; PHOSPHORYLATION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12806