Distinct IL-1α-responsive Enhancers Promote Acute and Coordinated Changes in Chromatin Topology in a Hierarchical Manner

EMBO J. 2020 Jan 2;39(1):e101533. doi: 10.15252/embj.2019101533. Epub 2019 Nov 7.

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.

Keywords: IL-8; NF-κB; chromatin topology; interleukin-1; tumor necrosis factor-α.

Publication types

  • Research Support, Non-U.S. Gov't

Associated data

  • GEO/GSE64224
  • GEO/GSE52470
  • GEO/GSE134436
  • SRA/PRJNA552438