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

• Sinah‐Sophia Weiterer ^[2] ; Johanna Meier‐Soelch ^[2] ; Theodore Georgomanolis ^[3] ; Athanasia Mizi ^[4] ; Anna Beyerlein ^[2] ; Hendrik Weiser ^[2] ; Lilija Brant ^[5] ; Christin Mayr‐Buro ^[2] ; Liane Jurida ^[2] ; Knut Beuerlein ^[2] ; Helmut Müller ^[2] ; Axel Weber ^[2] ; Ulas Tenekeci ^[2] ; Oliver Dittrich‐Breiholz ^[6] ; Marek Bartkuhn ^[7] ; Andrea Nist ^[8] ; Thorsten Stiewe ^[9] ; Wilfred FJ van IJcken ^[10] ; Tabea Riedlinger ^[11] ; M Lienhard Schmitz ^[1] ; Argyris Papantonis ^[4] ; Michael Kracht ^[12]
  1. [1] German Center for Lung Research

     German Center for Lung Research

     Distrito de Gießen, Alemania

     
  2. [2] 1 Rudolf Buchheim Institute of Pharmacology Justus Liebig University Giessen Giessen Germany
  3. [3] 2 Center for Molecular Medicine Cologne University of Cologne Cologne Germany
  4. [4] 2 Center for Molecular Medicine Cologne University of Cologne Cologne Germany; 3 Department of Pathology University Medical Center Göttingen Göttingen Germany
  5. [5] 3 Department of Pathology University Medical Center Göttingen Göttingen Germany
  6. [6] 4 Research Core Unit Genomics Institute of Physiological Chemistry Medical School Hannover Hannover Germany
  7. [7] 5 Institute for Genetics Justus Liebig University Giessen Giessen Germany
  8. [8] 6 Genomics Core Facility and Institute of Molecular Oncology Philipps University Marburg Marburg Germany
  9. [9] 6 Genomics Core Facility and Institute of Molecular Oncology Philipps University Marburg Marburg Germany; 7 Member of the German Center for Lung Research (DZL) Giessen Germany
  10. [10] 8 Center for Biomics Erasmus Medical Center Rotterdam The Netherlands
  11. [11] 9 Institute of Biochemistry Justus Liebig University Giessen Giessen Germany
  12. [12] 1 Rudolf Buchheim Institute of Pharmacology Justus Liebig University Giessen Giessen Germany; 7 Member of the German Center for Lung Research (DZL) Giessen Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 39, Nº. 1, 2020
• Idioma: inglés
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  • 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.