Co-expression networks uncover regulation of splicing and transcription markers of disease.

Abstract

Gene co-expression networks based on gene expression data are usually used to capture biologically significant patterns, enabling the discovery of biomarkers and interpretation of regulatory relationships. However, the coordination of numerous splicing changes within and across genes can exert a substantial impact on the function of these genes. This is particularly impactful in studies of the properties of the nervous system, which can be masked in the networks that only assess the correlation between gene expression levels. A bioinformatics approach was developed to uncover the role of alternative splicing and associated transcriptional networks using RNA-seq profiles. Data from 40 samples, including control and two treatments associated with sensitivity to stimuli across two central nervous system regions that can present differential splicing, were explored. The gene expression and relative isoform levels were integrated into a transcriptome-wide matrix, and then Graphical Lasso was applied to capture the interactions between genes and isoforms. Next, functional enrichment analysis enabled the discovery of pathways dysregulated at the isoform or gene levels and the interpretation of these interactions within a central nervous region. In addition, a Bayesian biclustering strategy was used to reconstruct treatment-specific networks from gene expression profile, allowing the identification of hub molecules and visualization of highly connected modules of isoforms and genes in specific conditions. Our bioinformatics approach can offer comparable insights into the discovery of biomarkers and therapeutic targets for a wide range of diseases and conditions.