Single cell RNA-seq uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19
Single cell RNA-seq uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19
Abstract The systemic immune response to viral infection is shaped by master transcription factors such as NFκB or PU.1. Although long non-coding 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-seq approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT 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, diverting the PU.1 transcription factor from alarmin promoters to dead-end pseudogenes in na?ve monocytes. NFκB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Our results suggest a major role of nuclear noncoding RNA circuits in systemic antiviral responses to SARS-CoV-2 in humans.
Bauer Christian、Hoppe Judith、Pauck Kim、Janga Harshavardhan、Volkers Sarah M、Aznaourova Marina、Georg Philipp、Mack Elisabeth、Skevaki Chrysanthi、Li Yang、Garn Holger、Wendisch Daniel、Schulte Leon N、Gruber Achim D、G¨1ndisch Margrit、Nist Andrea、Sander Leif E、Schmeck Bernd、Zhang Zhenhua、Schmerer Nils、Stiewe Thorsten、Ruppert Clemens、Keller Christian、Bertrams Wilhelm
Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg, UKGM, Philipps University MarburgInstitute of Veterinary Pathology, Freie Universitaet BerlinTranslational Inflammation Research Division & Core Facility for Single Cell Multiomics, Philipps University MarburgInstitute for Lung Research, Philipps University MarburgDepartment of Infectious Diseases and Respiratory Medicine, Charit¨|-Universit?tsmedizin Berlin, Corporate Member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of HealthInstitute for Lung Research, Philipps University MarburgDepartment of Infectious Diseases and Respiratory Medicine, Charit¨|-Universit?tsmedizin Berlin, Corporate Member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of HealthDepartment of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen and MarburgInstitute of Laboratory Medicine, Philipps University MarburgDepartment of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)||Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical CenterTranslational Inflammation Research Division & Core Facility for Single Cell Multiomics, Philipps University Marburg||German Center for Lung Research (DZL)Department of Infectious Diseases and Respiratory Medicine, Charit¨|-Universit?tsmedizin Berlin, Corporate Member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of HealthInstitute for Lung Research, Philipps University Marburg||German Center for Lung Research (DZL)Institute of Veterinary Pathology, Freie Universitaet BerlinInstitute of Laboratory Medicine, Philipps University MarburgGenomics Core Facility, Philipps University MarburgDepartment of Infectious Diseases and Respiratory Medicine, Charit¨|-Universit?tsmedizin Berlin, Corporate Member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of Health||German Center for Lung Research (DZL)Institute for Lung Research, Philipps University Marburg||German Center for Lung Research (DZL)||Department of Respiratory and Critical Care Medicine, University Medical Center Marburg||Center for Synthetic Microbiology (SYNMIKRO), Philipps University Marburg Member of the German Center of Infection Research (DZIF)Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)||Department of Genetics, University of Groningen and University Medical Center GroningenInstitute for Lung Research, Philipps University MarburgGenomics Core Facility, Philipps University Marburg||Institute of Molecular Oncology, Philipps University Marburg||German Center for Lung Research (DZL)German Center for Lung Research (DZL)||UGMLC-Giessen Biobank & Pneumologic Patient Registry||Universities of Giessen and Marburg Lung Center (UGMLC)Institute of Virology, University Hospital Giessen and MarburgInstitute for Lung Research, Philipps University Marburg
基础医学生物科学研究方法、生物科学研究技术分子生物学
Bauer Christian,Hoppe Judith,Pauck Kim,Janga Harshavardhan,Volkers Sarah M,Aznaourova Marina,Georg Philipp,Mack Elisabeth,Skevaki Chrysanthi,Li Yang,Garn Holger,Wendisch Daniel,Schulte Leon N,Gruber Achim D,G¨1ndisch Margrit,Nist Andrea,Sander Leif E,Schmeck Bernd,Zhang Zhenhua,Schmerer Nils,Stiewe Thorsten,Ruppert Clemens,Keller Christian,Bertrams Wilhelm.Single cell RNA-seq uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19[EB/OL].(2025-03-28)[2025-07-21].https://www.biorxiv.org/content/10.1101/2021.11.05.467458.点此复制
评论