Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

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 th...

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Vydané v:	Nature communications Ročník 12; číslo 1; s. 6115 - 12
Hlavní autori:	Aneas, Ivy, Decker, Donna C., Howard, Chanie L., Sobreira, Débora R., Sakabe, Noboru J., Blaine, Kelly M., Stein, Michelle M., Hrusch, Cara L., Montefiori, Lindsey E., Tena, Juan, Magnaye, Kevin M., Clay, Selene M., Gern, James E., Jackson, Daniel J., Altman, Matthew C., Naureckas, Edward T., Hogarth, Douglas K., White, Steven R., Gomez-Skarmeta, Jose Luis, Schoetler, Nathan, Ober, Carole, Sperling, Anne I., Nóbrega, Marcelo A.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 21.10.2021 Nature Publishing Group Nature Portfolio
Predmet:	38/39 45/43 45/77 49/109 631/208/200 631/208/205/2138 631/250/127/1213 64/110 64/116 96/35 Alleles Animals Asthma Asthma - genetics Asthma - metabolism Blood plasma Chromatin Chromatin - genetics Chromatin - metabolism Enhancer Elements, Genetic Epithelial cells Epithelium Female Gene expression Genetic diversity Genetic Predisposition to Disease Genetic variance Genome-wide association studies Health risks Humanities and Social Sciences Humans Interleukin-33 - genetics Interleukin-33 - metabolism Loci Male Mice, Transgenic multidisciplinary Nucleotides Oct-1 protein Octamer Transcription Factor-1 - genetics Octamer Transcription Factor-1 - metabolism Polymorphism Polymorphism, Single Nucleotide Promoter Regions, Genetic Science Science (multidisciplinary) Signs and symptoms Single-nucleotide polymorphism Zebrafish
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	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. Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-26347-z