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

Overview of attention for article published in Science Advances, February 2018
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  • Above-average Attention Score compared to outputs of the same age (63rd percentile)

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Title
Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1
Published in
Science Advances, February 2018
DOI 10.1126/sciadv.1701729
Pubmed ID
Authors

Robert-Jan Palstra, Elisa de Crignis, Michael D Röling, Thomas van Staveren, Tsung Wai Kan, Wilfred van Ijcken, Yvonne M Mueller, Peter D Katsikis, Tokameh Mahmoudi

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-32α to non-α 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-32γ (rIL-32γ) but not rIL-32α, and exogenous lentiviral overexpression of IL-32γ or IL-32β but not IL-32α 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-32α 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.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 35 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 35 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 20%
Researcher 6 17%
Student > Master 5 14%
Student > Doctoral Student 4 11%
Student > Bachelor 3 9%
Other 6 17%
Unknown 4 11%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 7 20%
Immunology and Microbiology 7 20%
Agricultural and Biological Sciences 7 20%
Medicine and Dentistry 6 17%
Chemistry 2 6%
Other 1 3%
Unknown 5 14%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 September 2019.
All research outputs
#7,359,319
of 25,382,440 outputs
Outputs from Science Advances
#9,916
of 12,215 outputs
Outputs of similar age
#121,415
of 344,362 outputs
Outputs of similar age from Science Advances
#181
of 231 outputs
Altmetric has tracked 25,382,440 research outputs across all sources so far. This one has received more attention than most of these and is in the 69th percentile.
So far Altmetric has tracked 12,215 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 120.3. This one is in the 18th percentile – i.e., 18% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 344,362 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 63% of its contemporaries.
We're also able to compare this research output to 231 others from the same source and published within six weeks on either side of this one. This one is in the 20th percentile – i.e., 20% of its contemporaries scored the same or lower than it.