Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure

Roy Oelen, Dylan H. Vries, Harm Brugge, M. Grace Gordon, Martijn Vochteloo, Chun J. Ye, Harm-Jan Westra, Lude Franke () and Monique G. P. Wijst ()
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Roy Oelen: University of Groningen, University Medical Center Groningen
Dylan H. Vries: University of Groningen, University Medical Center Groningen
Harm Brugge: University of Groningen, University Medical Center Groningen
M. Grace Gordon: University of California San Francisco
Martijn Vochteloo: University of Groningen, University Medical Center Groningen
Chun J. Ye: Institute for Human Genetics, University of California San Francisco
Harm-Jan Westra: University of Groningen, University Medical Center Groningen
Lude Franke: University of Groningen, University Medical Center Groningen
Monique G. P. Wijst: University of Groningen, University Medical Center Groningen

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The host’s gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host’s genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.

Date: 2022
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DOI: 10.1038/s41467-022-30893-5

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