Circular RNA Expression and Interaction Patterns Are Perturbed in Amyotrophic Lateral Sclerosis

Abstract

Circular RNAs (circRNAs) are a type of long noncoding RNA that are highly abundant and highly conserved throughout evolution and exhibit differential expression patterns in various tissue types in multiple diseases, including amyotrophic lateral sclerosis (ALS). The most well-known function of circRNAs is their ability to act as microRNA (miRNA) sponges. This entails circRNA binding to miRNA, which would otherwise target and degrade messenger RNA, thus affecting gene expression. This study analyzed ALS patient samples from three spinal cord regions to investigate circular transcriptome perturbation and circular RNA-microRNA-mRNA interactions. Using stringent statistical parameters, we identified 92 differentially expressed circRNAs across the spinal cord tissues with the aim of identifying specific circRNAs with biomarker potential. We also found evidence for differential expression of 37 linear RNAs possibly due to miRNA sequestration by circRNAs, thus revealing their potential as novel biomarkers and therapeutic candidates for ALS.

Keywords: amyotrophic lateral sclerosis; circular RNAs; microRNAs; spinal cord; transcriptome sequencing.

Figure 1

Heatmap of GO terms of the mRNA targets of 12 miRNAs. Heatmap showing which GO terms are associated with each miRNA and the colors associated with the p value for the miRNA/GO term pair.

Figure 2

Network of circRNA–miRNA–mRNA interactions. A tripartite network graph displaying DE circRNAs (left), targeted miRNAs (middle) and targeted mRNAs (right), and the interactions between species. The node size equates to the log₂ transformation of the number of interactions associated with each node, and the interaction line color relates to the associated miRNA. The green-colored circRNAs originated from SCC tissue, and the blue-colored circRNAs originated from SCT tissue.