Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
| العنوان: | Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region |
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| المؤلفون: | Steven R. White, Juan J. Tena, James E. Gern, Débora R. Sobreira, Chanie L. Howard, Kevin M. Magnaye, Carole Ober, Kelly M. Blaine, José Luis Gómez-Skarmeta, Noboru J. Sakabe, Cara L. Hrusch, Anne I. Sperling, Michelle M. Stein, Marcelo A. Nobrega, Edward T. Naureckas, Donna C. Decker, Ivy Aneas, Nathan Schoetler, Lindsey E. Montefiori, Daniel J. Jackson, Douglas K. Hogarth, Matthew C. Altman, Selene M. Clay |
| المساهمون: | National Institutes of Health (US) |
| المصدر: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Science, General Physics and Astronomy, Mice, Transgenic, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Chromosome conformation capture, Gene expression, Animals, Humans, Genetic Predisposition to Disease, Allele, Promoter Regions, Genetic, Enhancer, Alleles, Zebrafish, Genetic association, Genetics, Multidisciplinary, Interleukins, General Chemistry, Interleukin-33, Asthma, Chromatin, Gene regulation, Enhancer Elements, Genetic, Female, Octamer Transcription Factor-1 |
| الوصف: | Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma. This work was supported by NIH grants R01 HL118758, R01 HL128075, R01 HL119577, R01 HL085197, U19 AI095230, UG3 OD023282 and UM1 AI114271. |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::675806710a5bb89f7c09fc586438962cTest https://doi.org/10.1038/s41467-021-26347-zTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....675806710a5bb89f7c09fc586438962c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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