PuSH - Publication Server of Helmholtz Zentrum München: Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19.

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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)

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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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