Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19.

Autor:	Aznaourova M; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany., Schmerer N; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany., Janga H; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany., Zhang Z; Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany.; Department of Genetics, University of Groningen and University Medical Center Groningen, 9713 AV, Groningen, The Netherlands., Pauck K; Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Philipps University Marburg, 35043 Marburg, Germany., Bushe J; Institute of Veterinary Pathology, Freie Universitaet Berlin, 14195 Berlin, Germany., Volkers SM; Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany., Wendisch D; Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany., Georg P; Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany., Ntini E; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, GR-70013, Greece., Aillaud M; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany., Gündisch M; Institute of Laboratory Medicine, Philipps University Marburg, 35043 Marburg, Germany., Mack E; Department of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen and Marburg, 35043 Marburg, Germany., Skevaki C; Institute of Laboratory Medicine, Philipps University Marburg, 35043 Marburg, Germany.; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 35392 Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany., Keller C; Institute of Virology, University Hospital Giessen and Marburg, 35043 Marburg, Germany., Bauer C; Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital of Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany., Bertrams W; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany., Marsico A; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.; Institute for Computational Biology, Helmholtz Centre, 85764 Munich, Germany., Nist A; Genomics Core Facility, Philipps University Marburg, 35043 Marburg, Germany., Stiewe T; German Center for Lung Research (DZL), Giessen, 35392 Germany.; Genomics Core Facility, Philipps University Marburg, 35043 Marburg, Germany.; Institute of Molecular Oncology, Philipps University Marburg, 35043 Marburg, Germany., Gruber AD; Institute of Veterinary Pathology, Freie Universitaet Berlin, 14195 Berlin, Germany., Ruppert C; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 35392 Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany.; UGMLC Giessen Biobank and european IPF registry (eurIPFreg), Giessen, 35392 Germany., Li Y; Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany.; Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., Garn H; Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Philipps University Marburg, 35043 Marburg, Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany., Sander LE; Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany., Schmeck B; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany.; Department of Respiratory and Critical Care Medicine, University Medical Center Marburg, 35043 Marburg, Germany.; Center for Synthetic Microbiology, Philipps University Marburg, 35043 Marburg, Germany.; German Center of Infection Research, 35043 Marburg, Germany., Schulte LN; Institute for Lung Research, Philipps University Marburg, 35043 Marburg, Germany.; German Center for Lung Research (DZL), Giessen, 35392 Germany.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Sep 06; Vol. 119 (36), pp. e2120680119. Date of Electronic Publication: 2022 Aug 23.
DOI:	10.1073/pnas.2120680119
Abstrakt:	The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB-dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.
Databáze:	MEDLINE
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