Pathway-GPS and SIGORA: identifying relevant pathways based on the over-representation of their gene-pair signatures

Foroushani, Amir; Brinkman, Fiona S. L.; Lynn, David J.

doi:10.7717/peerj.229

Cited by 51 publications

(46 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Differential gene expression analysis was performed using the edgeR Bioconductor package that was customized to filter out all bovine rRNA genes, genes displaying expression levels below one count per million [CPM] in at least ten individual libraries and identify differentially expressed (DE) genes between all pairs of infection groups within each time point, correcting for multiple testing using the Benjamini-Hochberg method with Log 2 FC > 1 and < -1 and an FDR threshold of significance < 0.05 (44, 45). Cellular functions and pathways over-represented in DE gene lists were assessed using the SIGORA R package (46).…”

Section: Methodsmentioning

confidence: 99%

Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Malone

Rue-Albrecht

Magee

et al. 2017

Preprint

View full text Add to dashboard Cite

Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis in a range of mammals, including humans. A key feature of MTBC pathogens is their high degree of genetic identity, yet distinct host tropism. Notably, while Mycobacterium bovis is highly virulent and pathogenic for cattle, the human pathogen M. tuberculosis is attenuated in cattle. Previous research also suggests that host preference amongst MTBC members has a basis in host innate immune responses. To explore MTBC host tropism, we present in-depth profiling of the MTBC reference strains M. bovis AF2122/97 and M. tuberculosis H37Rv at both the global transcriptional and translational level via RNA-sequencing and SWATH mass spectrometry. Furthermore, a bovine alveolar macrophage infection time course model was employed to investigate the shared and divergent host transcriptomic response to infection with M. tuberculosis or M. bovis. Significant differential expression of virulence-associated pathways between the two bacilli was revealed, including the ESX-1 secretion system. A divergent transcriptional response was observed between M. tuberculosis and M. bovis infection of bovine alveolar macrophages, in particular cytosolic DNA-sensing pathways at 48 hours post-infection, and highlights a distinct engagement of M. bovis with the bovine innate immune system. The work presented here therefore provides a basis for the identification of host innate immune mechanisms subverted by virulent host-adapted mycobacteria to promote their survival during the early stages of infection.ImportanceThe Mycobacterium tuberculosis complex (MTBC) includes the most important global pathogens for humans and animals, namely Mycobacterium tuberculosis and Mycobacterium bovis, respectively. These two exemplar mycobacterial pathogens share a high degree of genetic identity, but the molecular basis for their distinct host preference is unknown. In this work we integrated transcriptomic and proteomic analyses of the pathogens to elucidate global quantitative differences between them at the mRNA and protein level. We then integrated this data with transcriptome analysis of the bovine macrophage response to infection with either pathogen. Increased expression of the ESX-1 virulence system in M. bovis appeared a key driver of an increased cytosolic nucleic acid sensing and interferon response in bovine macrophages infected with M. bovis compared to M. tuberculosis. Our work demonstrates the specificity of host-pathogen interaction and how the subtle interplay between mycobacterial phenotype and host response may underpin host specificity amongst MTBC members.

show abstract

Section: Methodsmentioning

confidence: 99%

Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Malone

Rue-Albrecht

Magee

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…Differential expression analysis was performed using DESeq2 v1.14.0 (31). Pathway enrichment was carried out using Sigora v2.0.1 (32), and network analysis was done by NetworkAnalyst (33). The genes in various inflammatory pathways were downloaded from InnateDB (34).…”

Section: Rna-seq Analysismentioning

confidence: 99%

Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model

Lee

Hancock

2017

The Journal of Immunology

View full text Add to dashboard Cite

Innate defense regulator (IDR) peptide-1002 is a synthetic host defense peptide derivative with strong anti-inflammatory properties. Extending previous data, IDR-1002 suppressed in vitro inflammatory responses in RAW 264.7 murine monocyte/macrophage cells challenged with the TLR4 agonist LPS and TLR2 agonists lipoteichoic acid and zymosan. To investigate the anti-inflammatory mechanisms of IDR-1002 in vivo, the PMA-induced mouse ear inflammation model was used. Topical IDR-1002 treatment successfully dampened PMA-induced ear edema, proinflammatory cytokine production, reactive oxygen and nitrogen species release, and neutrophil recruitment in the ears of CD1 mice. Advanced RNA transcriptomic analysis on the mouse ear transcriptome revealed that IDR-1002 reduced sterile inflammation by suppressing the expression of transmembrane G protein-coupled receptors (class A/1 rhodopsin-like), including receptors for chemokines, PGs, histamine, platelet activating factor, and anaphylatoxin. IDR-1002 also dampened the IFN-γ response and repressed the IFN regulatory factor 8-regulated network that controls central inflammatory pathways. This study demonstrates that IDR-1002 exhibits strong in vitro and in vivo anti-inflammatory activities, informs the underlying anti-inflammatory mechanisms, and reveals its potential as a novel therapeutic for inflammatory diseases.

show abstract

“…To characterize the biological functions of genes for which alternative splicing was associated with nearby SNPs, Sigora (32) was used to identify overrepresented pathways in genes that had sQTLs but not eQLTs. This method of pathway analysis focuses on genes or gene pairs that are specific to a single pathway.…”

Section: Resultsmentioning

confidence: 99%

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

Saferali

Yun

Parker

et al. 2019

Preprint

View full text Add to dashboard Cite

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD).RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 60% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1×10−6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2.Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.Author SummaryWhile it is known that chronic obstructive pulmonary disease (COPD) is caused in part by genetic factors, few studies have identified specific causative genes. Genetic variants that alter the expression levels of genes have explained part of the genetic component of COPD, however, there are additional genetic variants with unknown function. In some genes the protein coding sequence can be altered by a mechanism known as RNA splicing. We hypothesized that some genetic variants that are associated with risk of COPD contribute to the disease by altering RNA splicing. In this study, we identified genetic variants that are associated both with COPD risk and RNA splicing. In particular, we found that a COPD associated variant of previously unknown function may contribute to the inclusion of a new exon in the FBXO38 gene. These finding are significant because they indicate that analysis of RNA splicing can help identify genes that contribute to disease.

show abstract

Pathway-GPS and SIGORA: identifying relevant pathways based on the over-representation of their gene-pair signatures

Cited by 51 publications

References 47 publications

Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

Contact Info

Product

Resources

About