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Upon Microbial Challenge, Human Neutrophils Undergo Rapid Changes in Nuclear Architecture and Chromatin Folding to Orchestrate an Immediate Inflammatory Gene Program

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Upon Microbial Challenge, Human Neutrophils Undergo Rapid Changes in Nuclear Architecture and Chromatin Folding to Orchestrate an Immediate Inflammatory Gene Program Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program Matthew Denholtz,1,5 Yina Zhu,1,5 Zhaoren He,1 Hanbin Lu,1 Takeshi Isoda,1,4 Simon Döhrmann,2 Victor Nizet,2,3 and Cornelis Murre1 1Division of Biological Sciences, Department of Molecular Biology, University of California at San Diego, La Jolla, California 92039, USA; 2Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla, California 92093, USA; 3Skaggs School of Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA 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 neu- trophils 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: gene expression; inflammation; neutrophils; nuclear architecture] Supplemental material is available for this article. Received October 11, 2019; revised version accepted December 12, 2019. The organization of the human genome within the nucle- 2012). The heterochromatic compartment is highly en- us is central to the control of gene expression and thus cell riched at the nuclear lamina, whereas the euchromatic identity and function. At the largest scale, the genome is compartment is positioned in the nuclear interior (Kosak folded into chromosome territories that, with the excep- et al. 2002). tion of nucleoli, rarely intermingle. However, chromo- Loop domains are established in part by the CTCF pro- somes are not randomly distributed across the nucleus. tein (Dixon et al. 2012; Rao et al. 2014). Convergently ori- Large and gene-poor chromosomes are predominantly ented pairs of CTCF-bound loci can form CTCF-anchored positioned at the lamina, whereas small and gene-rich loops generated by recruitment of the cohesin complex chromosomes concentrate in the nuclear interior (Fritz (Nora et al. 2017; Rao et al. 2017). Cohesin is loaded et al. 2016). Chromosomes themselves fold into loop onto transcribed regions located throughout loop bodies domains that physically associate to establish the tran- (Busslinger et al. 2017). Once sequestered, the cohesin scriptionally repressive or inert heterochromatic B com- complex extrudes chromatin in a progressive manner un- partment or transcriptionally permissive euchromatic A til a pair of convergent CTCF-bound sites are reached, a compartment (Lieberman-Aiden et al. 2009; Dixon et al. process termed loop extrusion (Fudenberg et al. 2016). Gene promoters connected to transcriptional enhancers 4Present address: Department of Pediatrics and Developmental Biology, © 2020 Denholtz et al. This article is distributed exclusively by Cold Tokyo Medical and Dental University, Tokyo, Japan. Spring Harbor Laboratory Press for the first six months after the full-issue 5These authors contributed equally to this work. publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License Article published online ahead of print. Article and publication date are (Attribution-NonCommercial 4.0 International), as described at http://cre- online at http://www.genesdev.org/cgi/doi/10.1101/gad.333708.119. ativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 34:1–17 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Denholtz et al. by CTCF-mediated loops tend to be highly expressed (Rao pattern recognition receptors including cell-surface and et al. 2014), and CTCF occupancy at nearby sites contrib- endolysosomal Toll-like receptors (TLRs), C-type lectin utes to the maintenance of gene expression and stable receptors, and formyl peptide receptors, among others. chromatin structure (Nora et al. 2017; Rao et al. 2017; Once activated, a variety of downstream signaling path- Schwarzer et al. 2017; Bintu et al. 2018). Finally, recent ways converge on the NF-κB and AP1 transcription studies have demonstrated that cohesin-dependent loop- factors to induce an inflammatory gene program including ing is closely associated with the control of inducible the cytokines and chemokines IL-8/CXCL8, TNFα, IL-1β, gene expression (Bruno et al. 2018). IL-17, and IFNγ (Garcia-Romo et al. 2011; Thomas and Human neutrophils are abundant, short-lived circulat- Schroder 2013; Tecchio et al. 2014). ing white blood cells that are critical first-responders to The mechanisms by which pathogen-sensing pathways infection and tissue damage. Upon injury or infection, interface with the neutrophil genome to induce a rapid neutrophils exit the circulation via extravasation, migrate and stimulant-appropriate inflammatory gene expression toward damaged tissues or infectious foci, phagocytose program remain unclear. Here we found that human neu- small pathogens, release reactive oxygen and nitrogen spe- trophil genomes display highly segmented compartments cies, and extrude their chromatin as cytotoxic granule- and contracted heterochromatin when compared with laced extracellular traps (NETs). In addition to their direct human embryonic stem cells. Upon microbe encounter, role in killing invading pathogens, activated neutrophils a specific subset of modestly euchromatic subdomains, rapidly induce the expression of a wide range of cytokines spatially segregated from the highly euchromatic A com- and chemokines to orchestrate an immediate inflamma- partment, displayed strengthening of their euchromatic tory response (Ley et al. 2018). character, and relocalized from a perinuclear envelope The nuclei of polymorphonuclear (PMN) neutrophils position toward the nuclear interior. Prominent among are composed of multiple distinct but internally continu- the regions that repositioned during human neutrophil ous lobes allowing them to swiftly migrate between (para- activation were gene loci associated with an activated cellular route) or through (transcellular route) endothelial neutrophil-specific gene expression program. Microbial- cells that line blood vessels and interstitial spaces of induced changes in long-range chromatin interactions tissues while maintaining their nuclear integrity (Olins were globally associated with rapid loss of insulation at et al. 2009; Muller 2013; Rowat et al. 2013). The Lamin euchromatic subdomain boundaries, as well as the forma- B receptor (LBR) is an important determinant for imposing tion of de novo chromatin loops linking immune response a multi-lobular nuclear architecture on neutrophils (Hoff- genes to pre-existing and de novo formed transcriptional mann et al. 2002; Shultz et al. 2003). Neutrophils of mice enhancers. The loop-mediated juxtaposition of inflamma- deficient in the Lbr gene fail to adopt a multi-lobular nu- tory genes to transcriptional enhancers upon microbial clear shape (Shultz et al. 2003), and mouse neutrophilic exposure was closely associated with the deposition of cell lines lacking Lbr cannot form characteristic toroidal histone 3 lysine 27 acetylation (H3K27ac), an enhancer- nuclei during differentiation (Zhu et al. 2017). Similarly, associated histone modification and rapid loading (<3 h) humans with LBR mutations manifest the Pelger-Huët of the cohesin complex at the subset of enhancer elements anomaly, characterized by a reduction in nuclear lobe that control an inflammatory gene program. Based on number in granulocytes (Hoffmann et al. 2002). these observations, we propose that the microbe-induced Chromatin folding in murine neutrophils is highly en- transcriptional signature of activated neutrophils is driv- riched for remote genomic interactions, primarily involv- en by activated enhancer repertoires. Activated enhancers ing heterochromatic regions. These interactions span vast marked by elevated levels of H3K27Ac, in turn, rapidly genomic distances resulting in large-scale chromosome recruit the cohesin machinery to dictate changes in chro- condensation. Terminal differentiation of murine neutro- matin folding and nuclear positioning of genes associated phils is also associated with the relocation of centromeres, with an inflammatory gene program. pericentromeres, telomeres, LINE elements, and ribosom- al DNA from the nuclear interior to the nuclear lamina, a process that requires the Lbr
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