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ScRNA-seq analysis and functional characterization of myeloid lincRNAs differentially expressed during COVID-19

ABSTRACT: Myeloid cell differentiation and immune-activation is controlled by numerous regulators, keeping the activity of the immune system within tight physiological limits. The transcriptional circuitries governing human myeloid immunity during COVID-19, however, remain incompletely understood. Recently, long non-coding RNAs were found to play important roles in immune gene regulation. Here, we studied human myeloid lineage specific lncRNAs by bulk and single cell RNA-seq and identified PIRAT (a.k.a. LINC00211) as a nuclear regulator of human monocyte immunity during COVID-19. Loss- and gain-of-function studies using CRISPR/Cas9 and lentiviral transgene expression revealed PIRAT as a negative feedback regulator of PU.1 transcription factor activity, controlling the expression of the major alarmins S100A8 and A9. Both alarmins critically contribute to the immunopathologies observed in patients with severe COVID-19. Mechanistically, ChIRP-seq revealed PIRAT as a decoy RNA, fostering PU.1 binding to pseudogenes and inhibiting PU.1 binding to alarmin promoters. Down-regulation of PIRAT during COVID-19 thus releases a break on alarmin expression. Additionaly, we found the lncRNA LUCAT1 to promote alarmin expression during COVID-19, by promoting NFkB-target gene expression at the cost of the JAK/STAT pathway. Taken together, our data suggest that RNA-based gene expression control in the human myeloid immune cell lineage plays a critical role in human host defence against SARS-CoV-2 infection and in the development of severe COVID-19.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142503 | GEO | 2022/08/03

REPOSITORIES: GEO

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