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Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor binding sites

Overview of attention for article published in Clinical and Translational Medicine, March 2015
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Title
Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor binding sites
Published in
Clinical and Translational Medicine, March 2015
DOI 10.1186/s40169-015-0054-5
Pubmed ID
Authors

William R Swindell, Mrinal K Sarkar, Philip E Stuart, John J Voorhees, James T Elder, Andrew Johnston, Johann E Gudjonsson

Abstract

Psoriasis is a cytokine-mediated skin disease that can be treated effectively with immunosuppressive biologic agents. These medications, however, are not equally effective in all patients and are poorly suited for treating mild psoriasis. To develop more targeted therapies, interfering with transcription factor (TF) activity is a promising strategy. Meta-analysis was used to identify differentially expressed genes (DEGs) in the lesional skin from psoriasis patients (n = 237). We compiled a dictionary of 2935 binding sites representing empirically-determined binding affinities of TFs and unconventional DNA-binding proteins (uDBPs). This dictionary was screened to identify "psoriasis response elements" (PREs) overrepresented in sequences upstream of psoriasis DEGs. PREs are recognized by IRF1, ISGF3, NF-kappaB and multiple TFs with helix-turn-helix (homeo) or other all-alpha-helical (high-mobility group) DNA-binding domains. We identified a limited set of DEGs that encode proteins interacting with PRE motifs, including TFs (GATA3, EHF, FOXM1, SOX5) and uDBPs (AVEN, RBM8A, GPAM, WISP2). PREs were prominent within enhancer regions near cytokine-encoding DEGs (IL17A, IL19 and IL1B), suggesting that PREs might be incorporated into complex decoy oligonucleotides (cdODNs). To illustrate this idea, we designed a cdODN to concomitantly target psoriasis-activated TFs (i.e., FOXM1, ISGF3, IRF1 and NF-kappaB). Finally, we screened psoriasis-associated SNPs to identify risk alleles that disrupt or engender PRE motifs. This identified possible sites of allele-specific TF/uDBP binding and showed that PREs are disproportionately disrupted by psoriasis risk alleles. We identified new TF/uDBP candidates and developed an approach that (i) connects transcriptome informatics to cdODN drug development and (ii) enhances our ability to interpret GWAS findings. Disruption of PRE motifs by psoriasis risk alleles may contribute to disease susceptibility.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 37 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 37 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 9 24%
Student > Bachelor 7 19%
Researcher 4 11%
Student > Postgraduate 3 8%
Professor > Associate Professor 3 8%
Other 8 22%
Unknown 3 8%
Readers by discipline Count As %
Medicine and Dentistry 15 41%
Biochemistry, Genetics and Molecular Biology 6 16%
Agricultural and Biological Sciences 3 8%
Immunology and Microbiology 3 8%
Pharmacology, Toxicology and Pharmaceutical Science 2 5%
Other 2 5%
Unknown 6 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. 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 19 April 2015.
All research outputs
#20,273,512
of 22,805,349 outputs
Outputs from Clinical and Translational Medicine
#664
of 850 outputs
Outputs of similar age
#223,252
of 263,705 outputs
Outputs of similar age from Clinical and Translational Medicine
#11
of 12 outputs
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