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

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)-1? induces acute and widespread changes in chromatin accessibility via the TAK1 kinase and NF-?B 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-1?-inducible IL8 and CXCL1-3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL-1?/TAK1-inducible manner. Microdeletions of p65-binding sites in either of the two enhancers impair NF-?B 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-1? signaling, as well as for IL-8 and IL-6 secretion. CRISPR-guided transactivation of the IL8 locus or cross-TAD regulation by TNF?-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-?B.

SUBMITTER: Weiterer SS 

PROVIDER: S-EPMC6939198 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature