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

Aznaourova, Marina; Schmerer, Nils; Janga, Harshavardhan; Zhang , Zhenhua; Pauck, Kim; Bushe, Judith; 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.; Ruppert, Clemens; Li, Yang; Garn, Holger; Sander, Leif E.; Schmeck, Bernd; Schulte, Leon N.

doi:10.1073/pnas.2120680119

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

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Ntini, Evgenia
RNA Bioinformatics (Annalisa Marsico), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, GR-70013, Greece;

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Marsico, Annalisa
RNA Bioinformatics (Annalisa Marsico), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Computational Biology, Helmholtz Centre, 85764 Munich, Germany;

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Citation

Aznaourova, M., Schmerer, N., Janga, H., Zhang, Z., Pauck, K., Bushe, J., et al. (2022). Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19. Proceedings of the National Academy of Sciences of the United States of America, 119(36): e2120680119. doi:10.1073/pnas.2120680119.

Cite as: https://hdl.handle.net/21.11116/0000-000A-EBCF-5

Abstract

The systemic immune response to viral infection is shaped by master transcription fac-tors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs)have been suggested as important regulators of transcription factor activity, their contri-butions to the systemic immunopathologies observed during SARS-CoV-2 infectionhave remained unknown. Here, we employed a targeted single-cell RNA sequencingapproach to reveal lncRNAs differentially expressed in blood leukocytes during severeCOVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alar-min transcription) as a major PU.1 feedback-regulator in monocytes, governing the pro-duction of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockoutand transgene expression, combined with chromatin-occupancy profiling, characterizedPIRATasanucleardecoyRNA,keepingPU.1frombindingtoalarminpromotersandpromoting its binding to pseudogenes in naïve monocytes. NF-κB–dependent PIRATdown-regulation during COVID-19 consequently releases a transcriptional brake, fuelingalarmin production. Alarmin expression is additionally enhanced by the up-regulation ofthe lncRNA LUCAT1, which promotes NF-κB–dependentgeneexpressionattheexpenseof targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncod-ing RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.