Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19
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 observe...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-09, Vol.119 (36), p.1-e2120680119 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.2120680119 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2120680119</identifier><identifier>PMID: 35998224</identifier><language>eng</language><publisher>Washington: National Academy of Sciences</publisher><subject>Binding ; Biological Sciences ; Chromatin ; Coronaviruses ; COVID-19 ; Gene expression ; Gene sequencing ; Immune response ; Immune system ; Leukocytes ; Monocytes ; NF-κB protein ; Non-coding RNA ; Pathogenesis ; Pseudogenes ; PU.1 protein ; Ribonucleic acid ; RNA ; Severe acute respiratory syndrome coronavirus 2 ; Stat1 protein ; Transcription factors ; Viral diseases</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-09, Vol.119 (36), p.1-e2120680119</ispartof><rights>Copyright National Academy of Sciences Sep 6, 2022</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-32e9abf32b4216cae8a222aa58f91f1fb11d0ff1927901d8afff5078b6070fe83</citedby><cites>FETCH-LOGICAL-c398t-32e9abf32b4216cae8a222aa58f91f1fb11d0ff1927901d8afff5078b6070fe83</cites><orcidid>0000-0003-4948-9882 ; 0000-0002-3142-2850 ; 0000-0003-0134-7826 ; 0000-0001-6814-9344 ; 0000-0003-2399-4338 ; 0000-0002-0180-2529 ; 0000-0002-0476-9947 ; 0000-0001-5194-5635 ; 0000-0003-1349-0160 ; 0000-0002-0938-2469 ; 0000-0002-2767-3606 ; 0000-0002-1781-7127 ; 0000-0002-3834-9705 ; 0000-0003-4061-494X ; 0000-0002-0075-7199 ; 0000-0002-4502-0393</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9457492/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9457492/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Aznaourova, Marina</creatorcontrib><creatorcontrib>Schmerer, Nils</creatorcontrib><creatorcontrib>Janga, Harshavardhan</creatorcontrib><creatorcontrib>Zhang, Zhenhua</creatorcontrib><creatorcontrib>Pauck, Kim</creatorcontrib><creatorcontrib>Bushe, Judith</creatorcontrib><creatorcontrib>Volkers, Sarah M.</creatorcontrib><creatorcontrib>Wendisch, Daniel</creatorcontrib><creatorcontrib>Georg, Philipp</creatorcontrib><creatorcontrib>Ntini, Evgenia</creatorcontrib><creatorcontrib>Aillaud, Michelle</creatorcontrib><creatorcontrib>Gündisch, Margrit</creatorcontrib><creatorcontrib>Mack, Elisabeth</creatorcontrib><creatorcontrib>Skevaki, Chrysanthi</creatorcontrib><creatorcontrib>Keller, Christian</creatorcontrib><creatorcontrib>Bauer, Christian</creatorcontrib><creatorcontrib>Bertrams, Wilhelm</creatorcontrib><creatorcontrib>Marsico, Annalisa</creatorcontrib><creatorcontrib>Nist, Andrea</creatorcontrib><creatorcontrib>Stiewe, Thorsten</creatorcontrib><creatorcontrib>Gruber, Achim D.</creatorcontrib><creatorcontrib>Ruppert, Clemens</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Garn, Holger</creatorcontrib><creatorcontrib>Sander, Leif E.</creatorcontrib><creatorcontrib>Schmeck, Bernd</creatorcontrib><creatorcontrib>Schulte, Leon N.</creatorcontrib><title>Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19</title><title>Proceedings of the National Academy of Sciences - PNAS</title><description>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.</description><subject>Binding</subject><subject>Biological Sciences</subject><subject>Chromatin</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Leukocytes</subject><subject>Monocytes</subject><subject>NF-κB protein</subject><subject>Non-coding RNA</subject><subject>Pathogenesis</subject><subject>Pseudogenes</subject><subject>PU.1 protein</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Stat1 protein</subject><subject>Transcription factors</subject><subject>Viral 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RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-32e9abf32b4216cae8a222aa58f91f1fb11d0ff1927901d8afff5078b6070fe83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Binding</topic><topic>Biological 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Bernd</au><au>Schulte, Leon N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><date>2022-09-06</date><risdate>2022</risdate><volume>119</volume><issue>36</issue><spage>1</spage><epage>e2120680119</epage><pages>1-e2120680119</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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. 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| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2022-09, Vol.119 (36), p.1-e2120680119 |
| issn | 0027-8424 1091-6490 |
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| source | PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Binding Biological Sciences Chromatin Coronaviruses COVID-19 Gene expression Gene sequencing Immune response Immune system Leukocytes Monocytes NF-κB protein Non-coding RNA Pathogenesis Pseudogenes PU.1 protein Ribonucleic acid RNA Severe acute respiratory syndrome coronavirus 2 Stat1 protein Transcription factors Viral diseases |
| title | Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19 |
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