Publikationsdatenbank

Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19 (2022)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Aznaourova, Marina

Schmerer, Nils

Janga, Harshavardhan

Zhang, Zhenhua

Pauck, Kim

Bushe, Judith (WE 12)

Volkers, Sarah M.

Wendisch, Daniel

Georg, Philipp

Ntini, Evgenia

Aillaud, Michelle

Gündisch, Margrit

Mack, Elisabeth

Skevaki, Chrysanthi

Keller, Christian

Bauer, Christian

Bertrams, Wilhelm

Marsico, Annalisa

Nist, Andrea

Stiewe, Thorsten

Gruber, Achim D. (WE 12)

Ruppert, Clemens

Li, Yang

Garn, Holger

Sander, Leif E.

Schmeck, Bernd

Schulte, Leon N.

Quelle

Proceedings of the National Academy of Sciences of the United States of America

Bandzählung: 119

Heftzählung: 36

Seiten: Artikel e2120680119

ISSN: 1091-6490

Sprache

Englisch

Verweise

URL (Volltext): https://www.pnas.org/doi/full/10.1073/pnas.2120680119

DOI: 10.1073/pnas.2120680119

Pubmed: 35998224

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.