Transcription factor motifs associated with anterior insula gene-expression underlying mood disorder phenotypes

Abstract

Background: Mood disorders represent a major cause of morbidity and mortality worldwide but their pathophysiology remains obscure. Gene expression profiles, especially with regards to the interactive influence of genes within the expression profiles underlying pathological brain phenotypes associated with mood disorders remains largely undefined. Methods:Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from postmortem mood disorder samples and compared with unaffected control samples for RNA-sequencing identification of differentially expressed genes (DEGs) in a) bipolar disorder (BD; n=37), and b) major depressive disorder (MDD n=30) vs controls (n=33), and c) low vs high Axis-I comorbidity (a measure of psychiatric morbidity burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs. Results:We found that DEGs in BD-vs-controls, MDD-vs-controls, and high-vs-low Axis-I comorbidity burden were enriched for TF-motifs known to regulate expression of toll-like receptor signaling genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular, organ and brain developmental processes.Discussion: Robust image-guided transcriptomics was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. TF motifs were identified for immune, cellular, embryonic and neurodevelopmental processes. Conclusion:Our results provided novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.