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Downloaded from J Immunol Published Online 24 May 2021 Ol.2000624 NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment This information is current as of September 28, 2021. Giulia Lunazzi, Maria Buxadé, Marta Riera-Borrull, Laura Higuera, Sarah Bonnin, Hector Huerga Encabo, Silvia Gaggero, Diana Reyes-Garau, Carlos Company, Luca Cozzuto, Julia Ponomarenko, José Aramburu and Cristina López-Rodríguez Downloaded from J Immunol published online 24 May 2021 http://www.jimmunol.org/content/early/2021/05/24/jimmun ol.2000624 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2021/05/24/jimmunol.200062 Material 4.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 24, 2021, doi:10.4049/jimmunol.2000624 The Journal of Immunology fi NFAT5 Ampli es Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment ,1,2 ,2 ,3 ,3 Giulia Lunazzi,* Maria Buxade,* Marta Riera-Borrull,* Laura Higuera,* † *,4 *,5 * Sarah Bonnin, Hector Huerga Encabo, Silvia Gaggero, Diana Reyes-Garau, †,6 † †,‡,§ ,7 Carlos Company, Luca Cozzuto, Julia Ponomarenko, Jose Aramburu,* ,7 and Cristina Lopez-Rodrı guez* The ability of innate immune cells to respond to pathogen-associated molecular patterns across a wide range of intensities is fundamental to limit the spreading of infections. Studies on transcription responses to pathogen-activated TLRs have often used Downloaded from relatively high TLR ligand concentrations, and less is known about their regulation under mild stimulatory conditions. We had shown that the transcription factor NFAT5 facilitates expression of antipathogen genes under TLR stimulation conditions corresponding to low pathogen loads. In this study, we analyze how NFAT5 optimizes TLR-activated responses in mouse macrophages. We show that NFAT5 was required for effective recruitment of central effectors p65/NF-kB and c-Fos to specific proinflammatory target genes, such as Nos2, Il6, and Tnf in primary macrophages responding to low doses of the TLR4 ligand LPS. By contrast, NFAT5 was not required for p65/NF-kB recruitment in response to high LPS doses. Using the transposase- http://www.jimmunol.org/ accessible chromatin with high-throughput sequencing assay, we show that NFAT5 facilitated chromatin accessibility mainly at promoter regions of multiple TLR4-responsive genes. Analysis of various histone marks that regulate gene expression in response to pathogens identified H3K27me3 demethylation as an early NFAT5-dependent mechanism that facilitates p65 recruitment to promoters of various TLR4-induced genes. Altogether, these results advance our understanding about specific mechanisms that optimize antipathogen responses to limit infections. The Journal of Immunology, 2021, 206: 116. he ability of sentinel cells such as macrophages to detect re- pathogen-associated molecular patterns in a wide range of concentra- duced loads of microbes allows immune defenses to limit tions and activate proinflammatory and antipathogen responses that the pathogen burden and curtail infections. This capacity de- are for the most part regulated by gene transcription (14). Although T fi different transcription factors participate in the response to TLR and by guest on September 28, 2021 pends on speci c sensors such as TLRs, which recognize a variety of *Immunology Unit, Department of Experimental and Health Sciences, Pompeu Fabra G.L. performed and analyzed most of the experimental work and drafted the University, Barcelona, Spain; †Centre for Genomic Regulation, Barcelona, Spain; figures. M.B. performed the in vivo peritoneal macrophage experiments, various ‡Barcelona Institute for Science and Technology, Barcelona, Spain; and xDepartment of chromatin immunoprecipitation (ChIP) assays, and experiments with H3K27me3 Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain inhibitors, and set up the protocols to prepare macrophage nuclei for tagmentation. M.R.-B., L.H., and D.R.-G. did additional ChIP and gene expression experiments 1Current address: Centro Nacional de Analisis Genomico, Barcelona, Spain. during the revision of the manuscript. S.B., L.C., and C.C. performed the 2G.L. and M.B. contributed equally to this work. bioinformatics analysis of the assay for transposase-accessible chromatin with high- throughput sequencing experiment and the NFAT5 motif search analysis. H.H.E. 3M.R.-B. and L.H. contributed equally to this work. set up the ChIP assays with anti-UTX Abs. S.G. contributed and analyzed the 4Current address: Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, histone acetylation experiments. J.P. supervised the bioinformatics analysis, London, U.K. provided feedback on data analysis interpretation, and reviewed the manuscript. J.A. provided critical advice, interpreted the data, prepared the figures, and edited 5Current address: Universite Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277- the manuscript. C.L.-R. designed and supervised the work, interpreted the data, CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France. prepared the figures, and wrote the manuscript. 6Current address: Max Delbruck€ Center for Molecular Medicine, Berlin, Germany. The sequences presented in this article have been submitted to the Gene Expression 7J.A. and C.L.-R. contributed equally to this work. Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE111476. ORCIDs: 0000-0001-6859-9505 (G.L.); 0000-0002-3020-8393 (M.B.); 0000-0003- Address correspondence and reprint requests to Dr. Cristina Lopez-Rodr ıguez and 4670-7290 (M.R.-B.); 0000-0001-7723-492X (L.H.); 0000-0001-5159-2518 (S.B.); Dr. Jose Aramburu, Pompeu Fabra University, C/Dr Aiguader No. 88, Barcelona 08003, 0000-0002-2685-1108 (S.G.); 0000-0003-3194-8892 (L.C.); 0000-0001-9279-9523 Spain. E-mail addresses: [email protected] (C.L.-R.) or jose.aramburu@ (J.A.); 0000-0002-2311-2406 (C.L.-R.). upf.edu (J.A.) Received for publication May 28, 2020. Accepted for publication March 17, 2021. The online version of this article contains supplemental material. This work was supported by the Spanish Ministry of Science and Innovation and Abbreviations used in this article: ATAC-seq, assay for transposase-accessible chromatin European Fund for Regional Development (RTI2018-095902-B-I00), Fundaciola Marato TV3 (201619-30), and the Marie Curie International Reintegration Programme with high-throughput sequencing; BMDM, bone marrow derived macrophage; ChIP, of the European Union (MCIRG516308 to C.L.-R.). Research in the laboratory of C.L.- chromatin immunoprecipitation; HDAC, histone deacetylase; iNOS, inducible NO R. and J.A. was also supported by the Generalitat de Catalunya (2017SGR888) and the synthase; PRC2, polycomb-repressive complex 2; RNA pol II, RNA polymerase II; RT- Spanish Ministry of Science Innovation and Universities through the “Unidad de qPCR, real-time quantitative PCR; TSA, trichostatin A; TSS, transcription start site; Excelencia Marıa de Maeztu” program funded by the Agencia Estatal de Investigacion- UTX, ubiquitously transcribed tetratricopeptide repeat X chromosome. AEI (CEX2018-000792-M). The Centre for Genomic Regulation acknowledges support This article is distributed under The American Association of Immunologists, Inc., of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Reuse Terms and Conditions for Author Choice articles. Severo Ochoa,” and the Centres de Recerca de Catalunya Programme of Generalitat de Catalunya. Additional funding to C.L.-R. was from the ICREA Academia Award of Institucio Catalana de Recerca i Estudis Avanc¸ats (Generalitat de Catalunya). Copyright © 2021 by The American Association of Immunologists, Inc. 0022-1767/21/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000624 The Journal of Immunology 2 considerable progress has been made in identifying their respective how NFAT5 endows macrophages with an amplification mechanism target genes, less is known about mechanisms involved in optimizing that optimizes their responsiveness to pathogens. transcription responses to reduced loads of pathogens, a capacity that is fundamental in the defense against infections. Materials and Methods Early work identified C/EBPd as a transcription factor particularly Mice relevant in the response to sustained high pathogen loads (5) and de- fi k d fi NFAT5-de cient mice have a deletion in the Nfat5 gene in the region encod- scribed that NF- B induced C/EBP expression ampli es the in- fi fl ing the rst exon of its DNA-binding domain
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