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

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...

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Autores principales:	Margot Brandt, Sarah Kim-Hellmuth, Marcello Ziosi, Alper Gokden, Aaron Wolman, Nora Lam, Yocelyn Recinos, Zharko Daniloski, John A Morris, Veit Hornung, Johannes Schumacher, Tuuli Lappalainen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/a9681609f382419c9c62501e1adfff8e
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spelling	oai:doaj.org-article:a9681609f382419c9c62501e1adfff8e2021-12-02T20:02:54ZAn autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?1553-73901553-740410.1371/journal.pgen.1009684https://doaj.org/article/a9681609f382419c9c62501e1adfff8e2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009684https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Functional 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.Margot BrandtSarah Kim-HellmuthMarcello ZiosiAlper GokdenAaron WolmanNora LamYocelyn RecinosZharko DaniloskiJohn A MorrisVeit HornungJohannes SchumacherTuuli LappalainenPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009684 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Margot Brandt Sarah Kim-Hellmuth Marcello Ziosi Alper Gokden Aaron Wolman Nora Lam Yocelyn Recinos Zharko Daniloski John A Morris Veit Hornung Johannes Schumacher Tuuli Lappalainen An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
description	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.
format	article
author	Margot Brandt Sarah Kim-Hellmuth Marcello Ziosi Alper Gokden Aaron Wolman Nora Lam Yocelyn Recinos Zharko Daniloski John A Morris Veit Hornung Johannes Schumacher Tuuli Lappalainen
author_facet	Margot Brandt Sarah Kim-Hellmuth Marcello Ziosi Alper Gokden Aaron Wolman Nora Lam Yocelyn Recinos Zharko Daniloski John A Morris Veit Hornung Johannes Schumacher Tuuli Lappalainen
author_sort	Margot Brandt
title	An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title_short	An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title_full	An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title_fullStr	An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title_full_unstemmed	An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title_sort	autoimmune disease risk variant: a trans master regulatory effect mediated by irf1 under immune stimulation?
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a9681609f382419c9c62501e1adfff8e
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An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?

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