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An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. METHODS: We...

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Autores principales: Kubota, Naoto, Suyama, Mikita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977261/
https://www.ncbi.nlm.nih.gov/pubmed/31969149
http://dx.doi.org/10.1186/s12920-020-0662-9
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author Kubota, Naoto
Suyama, Mikita
author_facet Kubota, Naoto
Suyama, Mikita
author_sort Kubota, Naoto
collection PubMed
description BACKGROUND: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. METHODS: We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants. RESULTS: We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels. CONCLUSIONS: The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data.
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spelling pubmed-69772612020-01-28 An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer Kubota, Naoto Suyama, Mikita BMC Med Genomics Research Article BACKGROUND: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. METHODS: We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants. RESULTS: We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels. CONCLUSIONS: The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data. BioMed Central 2020-01-22 /pmc/articles/PMC6977261/ /pubmed/31969149 http://dx.doi.org/10.1186/s12920-020-0662-9 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Kubota, Naoto
Suyama, Mikita
An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title_full An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title_fullStr An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title_full_unstemmed An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title_short An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer
title_sort integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range errfi1 enhancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977261/
https://www.ncbi.nlm.nih.gov/pubmed/31969149
http://dx.doi.org/10.1186/s12920-020-0662-9
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