PUBLICATION
Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
- Authors
- Aneas, I., Decker, D.C., Howard, C.L., Sobreira, D.R., Sakabe, N.J., Blaine, K.M., Stein, M.M., Hrusch, C.L., Montefiori, L.E., Tena, J., Magnaye, K.M., Clay, S.M., Gern, J.E., Jackson, D.J., Altman, M.C., Naureckas, E.T., Hogarth, D.K., White, S.R., Gomez-Skarmeta, J.L., Schoetler, N., Ober, C., Sperling, A.I., Nóbrega, M.A.
- ID
- ZDB-PUB-211216-6
- Date
- 2021
- Source
- Nature communications 12: 6115 (Journal)
- Registered Authors
- Tena, Juan
- Keywords
- none
- MeSH Terms
-
- Alleles
- Animals
- Asthma/genetics*
- Asthma/metabolism
- Chromatin/genetics
- Chromatin/metabolism
- Enhancer Elements, Genetic*
- Female
- Genetic Predisposition to Disease
- Humans
- Interleukin-33/genetics*
- Interleukin-33/metabolism
- Male
- Mice, Transgenic
- Octamer Transcription Factor-1/genetics
- Octamer Transcription Factor-1/metabolism
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Zebrafish
- PubMed
- 34675193 Full text @ Nat. Commun.
Citation
Aneas, I., Decker, D.C., Howard, C.L., Sobreira, D.R., Sakabe, N.J., Blaine, K.M., Stein, M.M., Hrusch, C.L., Montefiori, L.E., Tena, J., Magnaye, K.M., Clay, S.M., Gern, J.E., Jackson, D.J., Altman, M.C., Naureckas, E.T., Hogarth, D.K., White, S.R., Gomez-Skarmeta, J.L., Schoetler, N., Ober, C., Sperling, A.I., Nóbrega, M.A. (2021) Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region. Nature communications. 12:6115.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping