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Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1.

ABSTRACT: We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4+ T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, and chromosome conformation capture assays identified a chromatin loop between rs4349147 and the IL-32 promoter validating its function as a long-distance enhancer. We generated single rs4349147-A or rs4349147-G allele clones and demonstrated that IL-32 enhancer activity and interaction with the IL-32 promoter are strongly allele dependent; rs4349147 -/A cells display reduced IL-32 expression and altered chromatin conformation as compared to rs4349147 G/- cells. Moreover, RNA sequencing demonstrated that rs4349147 G/- cells express a lower relative ratio of IL-32? to non-? isoforms than rs4349147 -/A cells and display increased expression of lymphocyte activation factors rendering them more prone to infection with HIV-1. In agreement, in primary CD4+ T cells, both treatment with recombinant IL-32? (rIL-32?) but not rIL-32?, and exogenous lentiviral overexpression of IL-32? or IL-32? but not IL-32? resulted in a proinflammatory T cell cytokine environment concomitant with increased susceptibility to HIV infection. Our data demonstrate that rs4349147-G promotes transcription of non-IL-32? isoforms, generating a proinflammatory environment more conducive to HIV infection. This study provides a mechanistic link between a HIV-associated noncoding DNA variant and the expression of different IL-32 isoforms that display discrete anti-HIV properties.

SUBMITTER: Palstra RJ

PROVIDER: S-EPMC5833994 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1.

Palstra Robert-Jan RJ de Crignis Elisa E Röling Michael D MD van Staveren Thomas T Kan Tsung Wai TW van Ijcken Wilfred W Mueller Yvonne M YM Katsikis Peter D PD Mahmoudi Tokameh T

Science advances 20180221 2

We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4<sup>+</sup> T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, a ...[more]

PMID: 29507875

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Project description:BackgroundInterleukin-32 (IL-32) has long been proposed as a biomarker for coronary artery disease (CAD). We aimed to evaluate the association between IL-32 levels and coronary stenosis severity, IL-32 polymorphisms rs28372698 and rs4786370, and CAD susceptibility.MethodsA total of 362 patients with definite or suspected CAD that underwent angiography were recruited (CAD group, n = 175; nonobstructive CAD group, n = 56; control group, n = 131). The severity of coronary stenosis was assessed using the Gensini score and the number of diseased vessels. IL-32 levels were determined using enzyme-linked immunosorbent assay. Gene polymorphisms were genotyped using PCR and sequencing techniques.ResultsIL-32 levels were significantly different at different levels of coronary artery stenosis (p < 0.05), and logIL-32 was positively correlated with the Gensini score (r = 0.357, p < 0.01). Multivariate logistic regression analysis revealed that IL-32 was independently associated with CAD (OR = 6.526, 95% CI: 3.344-12.739, p < 0.01). The receiver operating characteristic analysis revealed the area under the curve for discriminating the CAD and Gensini score were 0.605 and 0.613, respectively. Furthermore, IL-32 levels were significantly higher before percutaneous coronary intervention (PCI) than at 7 days post-PCI (p = 0.012). The homozygous TT genotype and T allele of rs28372698 were found to be associated with increased risk of CAD, while TT homozygosity and the T allele of rs4786370 with reduced risk of CAD (p < 0.05). However, both SNPs had no obvious effect on IL-32 levels or coronary stenosis severity in patients with CAD.ConclusionTo the best of our knowledge, our study is the first to show that rs28372698 and rs4786370 are associated with CAD susceptibility in Chinese Han population. We also suggest that plasma IL-32 levels may be indicative of coronary artery stenosis and the efficacy of PCI and provide guidance for risk stratification and disease management.

Dataset Information

Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1.

Publications

Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1.

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