MicroRNA Mediates Gene Regulation That Underlies JIA Pathology

Patients with juvenile idiopathic arthritis (JIA) and cystic fibrosis (CF) experience chronic, indolent inflammation that makes it difficult to determine whether their immunological abnormalities are truly pathological or a predictable, physiological adaptation to chronic inflammation in soft tissues. Researchers are developing tools to address this distinction. Specifically, projects from the National Institutes of Health, such as the Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomics, have made it possible to address the question of pathophysiology vs. immunological adaptation via eukaryote transcriptomes. Data from these large, complex studies would suggest that transcriptome analysis will allow for a network approach to describing pathogenesis. In particular, the studies have fueled a growing understanding of the role microRNA (miRNA) plays in the mediation of gene regulation via destabilizing target transcripts.

New research has leveraged insights into transcriptomes and shed light on the connection between genes, non-coding transcripts and disease phenotypes. Zihua Hu, PhD, a bioinformatics computational scientist of the State University of New York in Buffalo, and colleagues published the results of their transcriptome analysis online on June 7 in Scientific Reports.¹ They found that neutrophils have transcriptional repertoires that are specific to different pathological/physiological contexts and increased our understanding of the role of innate immunity in JIA pathology. Dr. Hu and colleagues demonstrated that miRNAs have a global effect on the neutrophil transcriptome, thereby revealing that cells known for their non-specific responses can tailor their transcriptional repertoire to specific physiologic and pathologic contexts.

“In this study, we examined transcriptional complexity in neutrophils of children with three distinct phenotypes: juvenile idiopathic arthritis, cystic fibrosis and healthy children seen in a well-child clinic,” write the authors in their paper. “We have previously shown that neutrophils of children with JIA show distinct transcriptional abnormalities that are associated with evidence of chronic activation and perturbation of fundamental metabolic processes. These transcriptional abnormalities do not correct when children achieve clinically inactive disease and maintain that state for six consecutive months.”

Based on this previous work, the investigators designed the current study, which used exon and miRNA hybridization-based microarrays to generate mRNA, gene isoform and miRNA expression profiles for the three phenotypes. They then performed hierarchical cluster analyses on the expression data from genes, isoforms and miRNA. When they performed enrichment analyses, they found that the differentially expressed genes in children with JIA were associated with alternative splicing, cytoskeleton, phosphoproteins and repeat regulatory proteins.

“We also demonstrate that the transcriptomes of neutrophils in chronic inflammatory states show extensive network ‘rewiring’ that is orchestrated by miRNA. The complexities of such miRNA-mRNA networks have been described previously, and even small variations in the number of miRNA molecules or their target mRNAs can have significant effects on network structure and protein translation,” explain the authors. Thus, their work, in combination with a previously published distinct network approach to understanding JIA, suggests a role for alternative splicing in JIA pathogenesis. The investigators acknowledge, however, that their data can provide only a snapshot of what is likely to be a highly complex and dynamic process.