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Distinct IL‐1α‐responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner
Author(s) -
Weiterer SinahSophia,
MeierSoelch Johanna,
Georgomanolis Theodore,
Mizi Athanasia,
Beyerlein Anna,
Weiser Hendrik,
Brant Lilija,
MayrBuro Christin,
Jurida Liane,
Beuerlein Knut,
Müller Helmut,
Weber Axel,
Tenekeci Ulas,
DittrichBreiholz Oliver,
Bartkuhn Marek,
Nist Andrea,
Stiewe Thorsten,
IJcken Wilfred FJ,
Riedlinger Tabea,
Schmitz M Lienhard,
Papantonis Argyris,
Kracht Michael
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019101533
Subject(s) - library science , art history , humanities , art , computer science
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 TAK 1 kinase and NF ‐κB at regions that are highly enriched for inflammatory disease‐relevant SNP s. Two enhancers in the extended chemokine locus on human chromosome 4 regulate the IL ‐1α‐inducible IL 8 and CXCL 1‐3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL ‐1α/ TAK 1‐inducible manner. Microdeletions of p65‐binding sites in either of the two enhancers impair NF ‐κB recruitment, suppress activation and biallelic transcription of the IL 8 / CXCL 2 genes, and reshuffle higher‐order chromatin interactions as judged by i4C interactome profiles. Notably, these findings support a dominant role of the IL 8 “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 IL 8 locus or cross‐ TAD regulation by TNF α‐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.