Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program

  1. Cornelis Murre1
  1. 1Division of Biological Sciences, Department of Molecular Biology, University of California at San Diego, La Jolla, California 92039, USA;
  2. 2Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla, California 92093, USA;
  3. 3Skaggs School of Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA
  1. Corresponding author: cmurre{at}ucsd.edu
  1. 5 These authors contributed equally to this work.

  • 4 Present address: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Differentiating neutrophils undergo large-scale changes in nuclear morphology. How such alterations in structure are established and modulated upon exposure to microbial agents is largely unknown. Here, we found that prior to encounter with bacteria, an armamentarium of inflammatory genes was positioned in a transcriptionally passive environment suppressing premature transcriptional activation. Upon microbial exposure, however, human neutrophils rapidly (<3 h) repositioned the ensemble of proinflammatory genes toward the transcriptionally permissive compartment. We show that the repositioning of genes was closely associated with the swift recruitment of cohesin across the inflammatory enhancer landscape, permitting an immediate transcriptional response upon bacterial exposure. We found that activated enhancers, marked by increased deposition of H3K27Ac, were highly enriched for cistromic elements associated with PU.1, CEBPB, TFE3, JUN, and FOSL2 occupancy. These data reveal how upon microbial challenge the cohesin machinery is recruited to an activated enhancer repertoire to instruct changes in chromatin folding, nuclear architecture, and to activate an inflammatory gene program.

Keywords

Footnotes

  • Received October 11, 2019.
  • Accepted December 12, 2019.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

| Table of Contents

Life Science Alliance