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. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.
Keywords: COVID-19; PU.1; immunity; long noncoding RNA; single-cell RNA-seq.
【저자키워드】 COVID-19, Immunity, single-cell RNA-seq., long noncoding RNA, PU.1, 【초록키워드】 Monocytes, SARS-CoV-2, Release, viral infection, severe COVID-19, SARS-COV-2 infection, Transcription, immunopathology, Single-cell RNA sequencing, RNA, COVID-19 pathogenesis, humans, single-cell RNA-seq, lncRNA, target, noncoding RNA, Stat1, expression, binding, NF-κB, JAK-STAT pathway, antiviral response, transcription factor, transcription factors, systemic immune response, knockout, naïve, down-regulation, blood leukocyte, pseudogene, promoter, transgene, nuclear, alarmin, approach, transcriptional, remained, characterized, suggested, promote, differentially expressed, driver, LUCAT1, NF-κB-dependent gene, 【제목키워드】 monocyte, RNA sequencing, lincRNA, nuclear,