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Aznaourova, M.* ; Schmerer, N.* ; Janga, H.* ; Zhang, Z.* ; Pauck, K.* ; Bushe, J.* ; Volkers, S.M.* ; Wendisch, D.* ; Georg, P.* ; Ntini, E.* ; Aillaud, M.* ; Gündisch, M.* ; Mack, E.* ; Skevaki, C.* ; Keller, C.* ; Bauer, C.* ; Bertrams, W.* ; Marsico, A. ; Nist, A.* ; Stiewe, T.* ; Gruber, A.D.* ; Ruppert, C.* ; Li, Y.* ; Garn, H.* ; Sander, L.E.* ; Schulte, L.N.*

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

Proc. Natl. Acad. Sci. U.S.A. 119:e2120680119 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Covid-19 ; Pu.1 ; Immunity ; Long Noncoding Rna ; Single-cell Rna-seq
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 119, Heft: 36, Seiten: , Artikelnummer: e2120680119 Supplement: ,
Verlag National Academy of Sciences
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Förderungen Radboud University Medicle Centre
Juergen Manchot Foundation
Hessisches Ministerium für Wissenschaft und Kunst (Hessen State Ministry of Higher Education, Research and the Arts)
Deutsche Forschungsgemeinschaft (DFG)