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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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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 |
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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 |
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