REALGAR: a web app of integrated respiratory omics data.

MOTIVATION: In the post genome-wide association study (GWAS) era, omics techniques have characterized information beyond genomic variants to include cell and tissue type-specific gene transcription, transcription factor binding sites, expression quantitative trait loci (eQTL) and many other biological layers. Analysis of omics data and its integration has in turn improved the functional interpretation of disease-associated genetic variants. Over 170 000 transcriptomic and epigenomic datasets corresponding to studies of various cell and tissue types under specific disease, treatment and exposure conditions are available in the Gene Expression Omnibus resource. Although these datasets are valuable to guide the design of experimental validation studies to understand the function of disease-associated genetic loci, in their raw form, they are not helpful to experimental researchers who lack adequate computational resources or experience analyzing omics data. We sought to create an integrated re-source of tissue-specific results from omics studies that is guided by disease-specific knowledge to facilitate the design of experiments that can provide biologically meaningful insights into genetic associations. RESULTS: We designed the Reducing Associations by Linking Genes and omics Results web app to provide multi-layered omics information based on results from GWAS, transcriptomic, epigenomic and eQTL studies for gene-centric analysis and visualization. With a focus on asthma datasets, the integrated omics results it contains facilitate the formulation of hypotheses related to airways disease-associated genes and can be addressed with experimental validation studies. AVAILABILITY AND IMPLEMENTATION: The REALGAR web app is available at: http://realgar.org/. The source code is available at: https://github.com/HimesGroup/realgar. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Multiomics analysis identifies BIRC3 as a novel glucocorticoid response-associated gene.

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. METHODS: Variants with P values less than 10-4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor- and (2) RNA polymerase II-binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. RESULTS: Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor-binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P < .05) with ICS response in 3 independent studies and others with asthma in 1 study. CONCLUSIONS: BIRC3 should be prioritized for further functional studies of ICS response.

Splicing Characteristics of Dystrophin Pseudoexons and Identification of a Novel Pathogenic Intronic Variant in the DMD Gene.

Pseudoexon (PE) inclusion has been implicated in various dystrophinopathies; however, its splicing characteristics have not been fully investigated. This study aims to analyze the splicing characteristics of dystrophin PEs and compare them with those of dystrophin canonical exons (CEs). Forty-two reported dystrophin PEs were divided into a splice site (ss) group and a splicing regulatory element (SRE) group. Five dystrophin PEs with characteristics of poison exons were identified and categorized as the possible poison exon group. The comparative analysis of each essential splicing signal among different groups of dystrophin PEs and dystrophin CEs revealed that the possible poison exon group had a stronger 3' ss compared to any other group. As for auxiliary SREs, different groups of dystrophin PEs were found to have a smaller density of diverse types of exonic splicing enhancers and a higher density of several types of exonic splicing silencers compared to dystrophin CEs. In addition, the possible poison exon group had a smaller density of 3' ss intronic splicing silencers compared to dystrophin CEs. To our knowledge, our findings indicate for the first time that poison exons might exist in DMD (the dystrophin gene) and present with different splicing characteristics than other dystrophin PEs and CEs.

The Chemopreventive Peptide Lunasin Inhibits d-Galactose- Induced Experimental Cataract in Rats.

Oxidative damage to the constituents of the eye lens is a major mechanism in the initiation and development of cataract. Lunasin, a 43-amino acids chemoprevention peptide, has been proved to possess potent anti-oxidative activity other than its established anticancer activities. Herein, we explored whether lunasin has preventative effects on d-galactose-induced experimental cataract in rat. After modeling, SD rats were administrated by instillation, 80 µM of lunasin eye drops to each eye thrice daily and consecutively for 30 days. As a result, lunasin treatment effectively inhibited the progression of d-galactose-induced experimental cataract, and protected the lenses of rats from oxidative damage and attenuated the lipid peroxidation through up-regulation of antioxidant enzymes, and inhibited the activation of polyol pathway by decreasing AR activity. Additionally, in vitro studies proved that lunasin treatment could protect human lens epithelial cells (hLECs) against d-galactose induced cell damage and apoptosis, and up-regulate antioxidant enzymes. This is the first demonstration that lunasin could inhibit d-galactose-induced experimental cataract in rats by protecting against oxidative damage and inhibiting the activation of polyol pathway.