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An allergy-associated polymorphism in a novel regulatory element enhances IL13 expression.

ABSTRACT: IL-13 is a central effector of Th2-mediated allergic inflammation and is critical for the induction of IgE synthesis. Common IL13 variants are associated with allergy phenotypes in populations of distinct ethnic background. We recently demonstrated that IL13 expression by human CD4+ T cells is paralleled by extensive IL13 locus remodeling, which results in the appearance of multiple DNase I hypersensitive sites. Among these, HS4 in the distal promoter is constitutive in both naïve and polarized Th1 and Th2 cells, and spans a common single nucleotide polymorphism, IL13-1512A>C (rs1881457), strongly associated with total serum IgE levels. We recently characterized HS4 as a novel cis-acting element that upregulates IL13 transcription in activated human and murine T cells. Here we show that IL13-1512A>C is a functional polymorphism that significantly enhances HS4-dependent IL13 expression by creating a binding site for the transcription factor Oct-1. Of note, endogenous Oct-1 was preferentially recruited to the IL13-1512C risk allele in primary CD4+ T cells from IL13-1512A>C heterozygous subjects. Moreover, the IL13-1512C allele was overexpressed in transfected Th2 cells from Oct1(+/+) mice, but not from Oct1(+/-) mice, demonstrating that increased activity was exquisitely dependent on physiologic levels of Oct-1. Our results illustrate how a functional variant in a regulatory element enhances transcription of an allergy-associated gene, thereby modulating disease susceptibility.

SUBMITTER: Kiesler P

PROVIDER: S-EPMC2773266 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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An allergy-associated polymorphism in a novel regulatory element enhances IL13 expression.

Kiesler Patricia P Shakya Arvind A Tantin Dean D Vercelli Donata D

Human molecular genetics 20090825 23

IL-13 is a central effector of Th2-mediated allergic inflammation and is critical for the induction of IgE synthesis. Common IL13 variants are associated with allergy phenotypes in populations of distinct ethnic background. We recently demonstrated that IL13 expression by human CD4+ T cells is paralleled by extensive IL13 locus remodeling, which results in the appearance of multiple DNase I hypersensitive sites. Among these, HS4 in the distal promoter is constitutive in both naïve and polarized ...[more]

PMID: 19706623

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Project description:CC chemokine ligand 2 (CCL2) is the most potent monocyte chemoattractant and inter-individual differences in its expression level have been associated with genetic variants mapping to the cis-regulatory regions of the gene. An A to G polymorphism in the CCL2 enhancer region at position -2578 (rs1024611; A>G), was found in most studies to be associated with higher serum CCL2 levels and increased susceptibility to a variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis. However, the precise mechanism by which rs1024611influences CCL2 expression is not known. To address this knowledge gap, we tested the hypothesis that rs1024611G polymorphism is associated with allelic expression imbalance (AEI) of CCL2. We used haplotype analysis and identified a transcribed SNP in the 3'UTR (rs13900; C>T) can serve as a proxy for the rs1024611 and demonstrated that the rs1024611G allele displayed a perfect linkage disequilibrium with rs13900T allele. Allele-specific transcript quantification in lipopolysaccharide treated PBMCs obtained from heterozygous donors showed that rs13900T allele were expressed at higher levels when compared to rs13900C allele in all the donors examined suggesting that CCL2 is subjected to AEI and that that the allele containing rs1024611G is preferentially transcribed. We also found that AEI of CCL2 is a stable trait and could be detected in newly synthesized RNA. In contrast to these in vivo findings, in vitro assays with haplotype-specific reporter constructs indicated that the haplotype bearing rs1024611G had a lower or similar transcriptional activity when compared to the haplotype containing rs1024611A. This discordance between the in vivo and in vitro expression studies suggests that the CCL2 regulatory region polymorphisms may be functioning in a complex and context-dependent manner. In summary, our studies provide strong functional evidence and a rational explanation for the phenotypic effects of the CCL2 rs1024611G allele.

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An allergy-associated polymorphism in a novel regulatory element enhances IL13 expression.

Publications

An allergy-associated polymorphism in a novel regulatory element enhances IL13 expression.

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