Distinct IL-1α-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner

SS Weiterer, J Meier-Soelch, T Georgomanolis, A Mizi, A Beyerlein, H Weiser, L Brant, C Mayr-Buro, L Jurida, K Beuerlein, H Muller, A Weber, U Tenekeci, O Dittrich-Breiholz, M Bartkuhn, A Nist, T Stiewe, Wilfred van Ijcken, T Riedlinger, ML SchmitzA Papantonis, M Kracht

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)
3 Downloads (Pure)


How cytokine-driven changes in chromatin topology are converted into gene regulatory circuits during inflammation still remains unclear. Here, we show that interleukin (IL)-1α induces acute and widespread changes in chromatin accessibility via the TAK1 kinase and NF-κB 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-1α-inducible IL8 and CXCL1-3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL-1α/TAK1-inducible manner. Microdeletions of p65-binding sites in either of the two enhancers impair NF-κB 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-1α signaling, as well as for IL-8 and IL-6 secretion. CRISPR-guided transactivation of the IL8 locus or cross-TAD regulation by TNFα-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-κB.
Original languageUndefined/Unknown
Article numbere101533
JournalEMBO Journal
Issue number1
Early online date7 Nov 2019
Publication statusPublished - 2 Jan 2020

Cite this