Gene co-expression network identifies critical genes, pathways and regulatory motifs mediating the progression of rift valley fever in Bostaurus

Abstract

Rift Valley Fever (RVF) is a mosquito-borne viral disease caused by the Rift Valley Fever Virus. The disease is a zoonosis that largely affects domestic animals, including sheep, goats, and cattle, resulting in severe morbidity and mortality marked by massive storm abortions. To halt human and livestock deaths due to RVF, the development of efficacious vaccines and therapeutics is a compelling and urgent priority. We sought to identify potential key modules (gene clusters), hub genes, and regulatory motifs involved in the pathogenesis of RVF in Bos taurus that are amenable to inhibition. We analyzed 39 Bos taurus RNA-Seq samples using the weighted gene co-expression network analysis (WGCNA) R package and uncovered significantly enriched modules containing genes with potential pivotal roles in RVF progression. Moreover, regulatory motif analysis conducted using the Multiple Expectation Maximization for Motif Elicitation (MEME) suite identified motifs that probably modulate vital biological processes. Gene ontology terms associated with identified motifs were inferred using the GoMo human database. The gene co-expression network constructed in WGCNA using 5000 genes contained seven (7) modules, out of which four were significantly enriched for terms associated with response to viruses, response to interferon-alpha, innate immune response, and viral defense. Additionally, several biological pathways implicated in developmental processes, anatomical structure development, and multicellular organism development were identified. Regulatory motifs analysis identified short, repeated motifs whose function(s) may be amenable to disruption by novel therapeutics. Predicted functions of identified motifs include tissue development, embryonic organ development, and organ morphogenesis. We have identified several hub genes in enriched co-expressed gene modules and regulatory motifs potentially involved in the pathogenesis of RVF in B. taurus that are likely viable targets for disruption by novel therapeutics.

Keywords: Bos taurus; Hub genes; Innate immune response; Modules; Regulatory motifs; Rift valley fever; weighted gene co-expression network.

Fig. 1

Gene clusters (modules) of MP-12 inoculated Bos taurus gene co-expression network. Each colour on the x-axis represents a gene module. WGCNA's dynamic tree cut function trims the gene dendrogram at different heights based on expression similarities (y-axis), resulting in 11 module colours (x-axis). The number of genes contained in each module is represented by the width of the different coloured modules at the bottom of the figure. The wider the colour bar, the more genes contained in the module.

Fig. 2

Number of genes contained in the gene modules. Each module is represented by the gene module colour. As shown in the pie chart, seven modules were identified. The black module contains 349 genes.

Fig. 3

An illustration of the interactions among components of the seven modules in the MP-12 inoculated Bos taurus gene co-expression network. Genes and interactions are depicted as nodes and edges respectively. Nodes are colour-coded to indicate their module membership. The gene co-expression network shown includes only genes with an interaction weight exceeding 0.05. This visualisation demonstrates the complexity of gene interactions in the MP-12 inoculated Bos taurus co-expression network. Only genes with significant co-expression relationships are shown.

Fig. 4

Interactions of the MS12 hub gene within the brown module with other genes.

Fig. 5

Interactions of the EIF2AK2 hub gene within the purple module.

Fig. 6

Interactions of the ERC2 hub gene within the turquoise module.

Fig. 7

Interactions of the TMSB10 hub gene within the blue module.