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

How cytokine-driven changes in chromatin topology are converted into gene regulatory circuits during inflammation still remains unclear. Here, we show that interleukin (IL)-1alpha induces acute and widespread changes in chromatin accessibility via the TAK1 kinase and NF-kappaB 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-1alpha-inducible IL8 and CXCL1-3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL-1alpha/TAK1-inducible manner. Microdeletions of p65-binding sites in either of the two enhancers impair NF-kappaB 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-1alpha signaling, as well as for IL-8 and IL-6 secretion. CRISPR-guided transactivation of the IL8 locus or cross-TAD regulation by TNFalpha-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-kappaB.

• Weiterer, S. S.
• Meier-Soelch, J.
• Georgomanolis, T.
• Mizi, A.
• Beyerlein, A.
• Weiser, H.
• Brant, L.
• Mayr-Buro, C.
• Jurida, L.
• Beuerlein, K.
• Muller, H.
• Weber, A.
• Tenekeci, U.
• Dittrich-Breiholz, O.
• Bartkuhn, M.
• Nist, A.
• Stiewe, T.
• van, IJcken W. F.
• Riedlinger, T.
• Schmitz, M. L.
• Papantonis, A.
• Kracht, M.