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 the brain-related molecular pathophysiology in 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) versus (vs.) controls (n=33), and b ) major depressive disorder (MDD n=30) vs controls, and c ) low vs. high Axis-I comorbidity (a measure of cumulative psychiatric disease 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 were associated with TF-motifs that are known to regulate expression of toll-like receptor genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular/organ and brain development. Discussion Robust imaging-guided transcriptomics (i.e., using meta-analytic imaging results to guide independent post-mortem dissection for RNA-sequencing) 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 findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provides novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.