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The Transcription Factor EGR2 Is the Molecular Linchpin Connecting STAT6 Activation to the Late, Stable Epigenomic Program of Alternative Macrophage Polarization

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The Transcription Factor EGR2 Is the Molecular Linchpin Connecting STAT6 Activation to the Late, Stable Epigenomic Program of Alternative Macrophage Polarization Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization Bence Daniel,1,2,3,11,12 Zsolt Czimmerer,4,12 Laszlo Halasz,1,2,3,12 Pal Boto,4 Zsuzsanna Kolostyak,4 Szilard Poliska,4 Wilhelm K. Berger,1,2,3 Petros Tzerpos,4 Gergely Nagy,4 Attila Horvath,4 György Hajas,5 Timea Cseh,4 Aniko Nagy,4 Sascha Sauer,6,7,8,9 Jean Francois-Deleuze,10 Istvan Szatmari,4 Attila Bacsi,5 and Laszlo Nagy1,2,3,4 1Department of Medicine, 2Department of Biological Chemistry, Johns Hopkins University School of Medicine, St. Petersburg, Florida 33701, USA; 3Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, Florida 33701, USA; 4Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; 5Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; 6Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany; 7CU Systems Medicine, University of Würzburg, Würzburg 97070, Germany; 8Berlin Institute for Medical Systems Biology, 9Berlin Institute of Health, Max-Delbrück- Center for Molecular Medicine, Berlin 13125, Germany; 10Centre National de Génotypage, Institut de Génomique, Commissariat à l’Énergie Atomique, Evry 91000, France Macrophages polarize into functionally distinct subtypes while responding to microenvironmental cues. The identity of proximal transcription factors (TFs) downstream from the polarization signals are known, but their ac- tivity is typically transient, failing to explain the long-term, stable epigenomic programs developed. Here, we mapped the early and late epigenomic changes of interleukin-4 (IL-4)-induced alternative macrophage polarization. We identified the TF, early growth response 2 (EGR2), bridging the early transient and late stable gene expression program of polarization. EGR2 is a direct target of IL-4-activated STAT6, having broad action indispensable for 77% of the induced gene signature of alternative polarization, including its autoregulation and a robust, downstream TF cascade involving PPARG. Mechanistically, EGR2 binding results in chromatin opening and the recruitment of chromatin remodelers and RNA polymerase II. Egr2 induction is evolutionarily conserved during alternative po- larization of mouse and human macrophages. In the context of tissue resident macrophages, Egr2 expression is most prominent in the lung of a variety of species. Thus, EGR2 is an example of an essential and evolutionarily conserved broad acting factor, linking transient polarization signals to stable epigenomic and transcriptional changes in macrophages. [Keywords: EGR2; IL-4; macrophage polarization; epigenomic regulation; transcription factor network] Supplemental material is available for this article. Received July 28, 2020; revised version accepted September 11, 2020. Macrophages (MFs) are integral parts of innate immunity to be regulated at three levels. The first level is a perma- and represent the first line of defense against invading nent program established by the developmental regu- pathogens. These activities require plasticity and rapid re- lation and is maintained by lineage-determining sponses to environmental cues, leading to the deployment transcription factors (LDTFs) like PU.1, CEBP, and AP-1. of epigenomic mechanisms resulting in specific and stable The second level is an adaptation to a given microenviron- gene expression programs. MF gene expression is thought ment brought about by distinct tissue-specific 11Present address: Department of Pathology, Stanford University School of © 2020 Daniel et al. This article is distributed exclusively by Cold Spring Medicine, Stanford 94305, California, USA. Harbor Laboratory Press for the first six months after the full-issue publi- 12These authors contributed equally to this work. cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (Attribu- Article published online ahead of print. Article and publication date are tion-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.343038.120. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 34:1–19 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Daniel et al. polarization signals (Amit et al. 2016; Guilliams et al. that act in a rapid and transient fashion. DNA binding of 2020) modulating TFs’ activity (Bonnardel et al. 2019); STAT6 alters the expression of hundreds of genes within i.e., singular polarizing cytokines such as IL-4 or IL-13 the first few hours of polarization, including several TFs. via signal transducer and activator of transcription 6 Due to its transient mechanism of action, the majority (STAT6). The third level of regulation takes place tran- of STAT6 is released from the chromatin after 24 h of cy- siently upon pathogen encounter or inflammatory stimu- tokine exposure (Czimmerer et al. 2018). Therefore, the lation (Glass and Natoli 2016). Therefore, MF polarization polarization program enters into a self-sustained, largely is part of normal physiologic processes, actively contribut- STAT6-independent stable state. This observation leads ing to controlling infection, cancer, and inflammatory to a so-far unresolved conundrum on how transiently act- disease progression (Lawrence and Natoli 2011). Conse- ing STAT6 induces a stable and sustained polarization quently, investigation of the polarization process became program. an intensely researched topic in immunology with thera- Several STAT6-induced TFs have been described as es- peutic ramifications. sential regulators of the alternative MF phenotype, in- The two end points of the contiguous spectrum of mac- cluding the peroxisome proliferator-activated receptor γ rophage polarization are the classical polarization of mac- (PPARG) (Odegaard et al. 2007), KLF4 (Liao et al. 2011), rophages (M1 MFs) via TLR or inflammatory cytokine IRF4 (Satoh et al. 2010), MYC (Pello et al. 2012), and signaling such as interferon γ or at the opposite end of more recently BHLHE40 (Jarjour et al. 2019). The latter the spectrum, alternative polarization (M2 MFs) induced is reported to specifically control the proliferation of large by IL-4 or IL-13 (Murray et al. 2014). These two models peritoneal MFs when IL-4 is abundant (Jarjour et al. 2019). are widely used to learn about the molecular events of Our recent study suggests that the nuclear receptor polarization of MFs (Murray et al. 2014). Functionally, PPARG is a late regulator of the alternative polarization classically polarized MFs are characterized by high anti- program via ligand-regulated gene expression and tran- microbial activities critical for host defense, while alter- scriptional memory. Importantly, neither of these TFs natively polarized MFs exhibit a characteristically more possess widespread regulatory roles when MFs transit anti-inflammatory profile contributing to tissue-regenera- from the early to late polarization state (Daniel et al. tion, tissue-remodeling, and the resolution of inflamma- 2018a). tion (Shapouri-Moghaddam et al. 2018). The in vivo Although the listed TFs are induced by STAT6 and their roles of alternatively polarized MFs are highlighted in al- expression is sustained beyond STAT6’s presence, their veolar MFs in the steady-state and different pathological action is highly specific, controlling very confined parts conditions including asthma and allergies, parasite infec- of the broad polarization program. Therefore, there is a tion, fibrosis, and cancer (Gordon and Martinez 2010; hiatus in our understanding, leading to the proposition Cohen et al. 2018) . The cytokines IL-4 or IL-13 are the ini- that broader epigenomic mechanism(s) and/or factor(s) tiators of this stable gene expression program and cellular directly controlled by STAT6 must exist, acting as molec- phenotype in its purest form and phosphorylated STAT6 ular linchpin(s) to link the early transient and late stable acts as a downstream immediate transcriptional regula- molecular events of polarization. tor. STAT6 is required for alternative polarization by IL- We took an unbiased systematic approach in the search 4 in bone marrow-derived macrophages (BMDM) and in for such epigenomic regulators, integrating both the map- vivo to mount effective antihelminth defense (Rückerl ping of genome activity patterns and de novo motif analy- and Allen 2014). However, the requirements and contri- sis. Using the combination of P300 (general coactivator bution of myeloid or macrophage STAT6 are not as well with histone acetyltransferase activity) and H3K27ac understood due to the lack of genetic evidence establish- chromatin immunoprecipitation sequencing (ChIP-seq), ing MF cell-autonomous function, as well as establishing we defined the early and late genome activity patterns of the contribution of the various aspects of Th2 immune alternative polarization in BMDMs. Our analyses, which responses. Thus, BMDM represents the gold standard included genetic gain and loss-of-function studies, identi- model to study the epigenomic and molecular
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