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

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

doi:10.1101/2021.11.05.467458

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bioRxiv · 10.1101/2021.11.05.467458

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

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Abstract

The systemic immune response to viral infection is shaped by master transcription factors such as NF{kappa}B 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 naive monocytes. NF{kappa}B-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.

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Aznaourova, M., Schmerer, N., Janga, H., Zhang, Z., Pauck, K., Hoppe, J., Volkers, S. M., Wendisch, D., Georg, P., Guendisch, M., Mack, E., Skevaki, C., Keller, C., Bauer, C., Bertrams, W., Nist, A., Stiewe, T., Gruber, A. D., Ruppert, C., Li, Y., Garn, H., Sander, L. E., Schmeck, B., Schulte, L. N.. 2021-11-05. Single cell RNA-seq uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19. https://doi.org/10.1101/2021.11.05.467458

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