Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Brandt, Margot, Kim-Hellmuth, Sarah, Ziosi, Marcello, Gokden, Alper, Wolman, Aaron, Lam, Nora, Recinos, Yocelyn, Daniloski, Zharko, Morris, John A., Hornung, Veit, Schumacher, Johannes, Lappalainen, Tuuli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345867/
https://www.ncbi.nlm.nih.gov/pubmed/34314424
http://dx.doi.org/10.1371/journal.pgen.1009684
_version_ 1783734731530043392
author Brandt, Margot
Kim-Hellmuth, Sarah
Ziosi, Marcello
Gokden, Alper
Wolman, Aaron
Lam, Nora
Recinos, Yocelyn
Daniloski, Zharko
Morris, John A.
Hornung, Veit
Schumacher, Johannes
Lappalainen, Tuuli
author_facet Brandt, Margot
Kim-Hellmuth, Sarah
Ziosi, Marcello
Gokden, Alper
Wolman, Aaron
Lam, Nora
Recinos, Yocelyn
Daniloski, Zharko
Morris, John A.
Hornung, Veit
Schumacher, Johannes
Lappalainen, Tuuli
author_sort Brandt, Margot
collection PubMed
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 Online
Article
Text
id pubmed-8345867
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-83458672021-08-07 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 Lappalainen, Tuuli PLoS Genet Research Article 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. Public Library of Science 2021-07-27 /pmc/articles/PMC8345867/ /pubmed/34314424 http://dx.doi.org/10.1371/journal.pgen.1009684 Text en © 2021 Brandt et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Brandt, Margot
Kim-Hellmuth, Sarah
Ziosi, Marcello
Gokden, Alper
Wolman, Aaron
Lam, Nora
Recinos, Yocelyn
Daniloski, Zharko
Morris, John A.
Hornung, Veit
Schumacher, Johannes
Lappalainen, Tuuli
An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
title 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_short 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?
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345867/
https://www.ncbi.nlm.nih.gov/pubmed/34314424
http://dx.doi.org/10.1371/journal.pgen.1009684
work_keys_str_mv AT brandtmargot anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT kimhellmuthsarah anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT ziosimarcello anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT gokdenalper anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT wolmanaaron anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT lamnora anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT recinosyocelyn anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT daniloskizharko anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT morrisjohna anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT hornungveit anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT schumacherjohannes anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT lappalainentuuli anautoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT brandtmargot autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT kimhellmuthsarah autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT ziosimarcello autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT gokdenalper autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT wolmanaaron autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT lamnora autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT recinosyocelyn autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT daniloskizharko autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT morrisjohna autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT hornungveit autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT schumacherjohannes autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation
AT lappalainentuuli autoimmunediseaseriskvariantatransmasterregulatoryeffectmediatedbyirf1underimmunestimulation