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

Sinah-Sophia Weiterer ,Marek Bartkuhn,Liane Jurida,Knut Beuerlein,Lilija Brant,Michael Kracht,Argyris Papantonis,Anna Beyerlein,Ulas Tenekeci,Thorsten Stiewe,Athanasia Mizi,Theodore Georgomanolis,Andrea Nist,Axel Weber,Tabea Riedlinger,Wilfred F J Van Ijcken ,H.‐Arno J Müller ,Johanna Meier-Soelch ,M Lienhard Schmitz ,Christin Mayr-Buro ,Oliver Dittrich‐Breiholz ,H Weiser

doi:10.15252/embj.2019101533

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.

Highlights

Inflammation is an evolutionarily conserved reaction to all forms of tissue injury and a major cause of human disease (Wallach et al, 2014)
We showed that induction is predominantly driven by NF-jB and that pharmacological inhibition of the TAK1 kinase suppresses most of the response (Jurida et al, 2015)
Widespread changes in accessibility along responsive loci such as IL8 and TNFAIP3 were observed (Fig 1A), and genome-wide, with > 75,000 (76,687) ATAC-seq peaks emerging in response to IL-1a stimulation. Accessibility at these IL-1a-induced peaks is abolished upon co-treatment with the TAK1 inhibitor and, dependent on TAK1mediated signaling (Fig 1B)

Summary

Introduction

Inflammation is an evolutionarily conserved reaction to all forms of tissue injury and a major cause of human disease (Wallach et al, 2014). All three pathways converge on regulating the nuclear concentration of TFs such as NF-jB and AP-1, thereby mediating cytokine-driven transcription at multiple responsive loci (Weber et al, 2010; Oeckinghaus et al, 2011; Zhang et al, 2017). While these modes of action are well established, a major unresolved question concerns the contribution of the non-coding genome to the coordinated IL-1/TNFa-triggered response in the three-dimensional (3D) space of the cell nucleus—i.e., how the various enhancers along chromosomes exert precise regulatory a 2019 The Authors.

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Conclusion