An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?

Brandt, Margot; Kim-Hellmuth, Sarah; Ziosi, Marcello; Gokden, Alper; Wolman, Aaron; Lam, Nora; Recinos, Yocelyn; Daniloski, Zharko; Morris, John A.; Hornung, Veit; Schumacher, Johannes und Lappalainen, Tuuli (2021): An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
In: PLOS Genetics 17(7), e1009684

Abstract

Author summary Although many genetic loci have been associated to disease, understanding how these variants impact molecular and cellular functions to impact disease risk have been challenging. Here, we first used blood cells from a large number of individuals and stimulated them in the laboratory with a proxy for bacterial infection. We identified that a genetic variant associated to autoimmune diseases also affects the expression of the nearby transcription factor IRF1 gene in early immune response, followed by expression change of other genes in late immune response. We then studied this effect in cell lines, using the CRISPR approach to silence the activity of the genomic element of this variant and cause mutations at that position. We found evidence that this autoimmune disease -associated variant is located in a genomic regulatory element that responds to immune stimulus and affects expression of IRF1 and a complex gene regulatory network. Thus, our characterization of genetic regulatory variation in the human population combined with experimental follow-up suggests a plausible, previously uncharacterized molecular mechanism that may underlie this genetic variant's effect on immune disease risk. Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56, affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect specific to IRF1 is active under early immune stimulus, with a large number of trans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that perturbation of the SNP locus downregulates IRF1 and causes widespread transcriptional effects. Genome editing by CRISPR had suggestive recapitulation of the LPS-specific trans-eQTL signal and lent support for the rs17622517 site being functional. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1. For this autoimmune GWAS locus, our work provides evidence of the functional variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatory trans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1553-7404
• Sprache: Englisch