Journal article

Authors list: Weiterer, SS; Meier-Soelch, J; Georgomanolis, T; Mizi, A; Beyerlein, A; Weiser, H; Brant, L; Mayr-Buro, C; Jurida, L; Beuerlein, K; Müller, H; Weber, A; Tenekeci, U; Dittrich-Breiholz, O; Bartkuhn, M; Nist, A; Stiewe, T; van IJcken, WF; Riedlinger, T; Schmitz, ML; Papantonis, A; Kracht, M

Publication year: 2020

Journal: The EMBO Journal

Volume number: 39

Issue number: 1

ISSN: 0261-4189

Open access status: Hybrid

DOI Link: https://doi.org/10.15252/embj.2019101533

Publisher: EMBO Press

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)-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.

Harvard Citation style: Weiterer, S., Meier-Soelch, J., Georgomanolis, T., Mizi, A., Beyerlein, A., Weiser, H., et al. (2020) Distinct IL-1α-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner, The EMBO Journal, 39(1), Article e101533. https://doi.org/10.15252/embj.2019101533

APA Citation style: Weiterer, S., Meier-Soelch, J., Georgomanolis, T., Mizi, A., Beyerlein, A., Weiser, H., Brant, L., Mayr-Buro, C., Jurida, L., Beuerlein, K., Müller, H., Weber, A., Tenekeci, U., Dittrich-Breiholz, O., Bartkuhn, M., Nist, A., Stiewe, T., van IJcken, W., Riedlinger, T., ...Kracht, M. (2020). Distinct IL-1α-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. The EMBO Journal. 39(1), Article e101533. https://doi.org/10.15252/embj.2019101533