Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes.

Abstract

Mood disorders represent a major cause of morbidity and mortality worldwide but the brain-related molecular pathophysiology in mood disorders remains largely undefined. Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from the anterior insula postmortem anterior insula ofmood disorder samples and compared with unaffected controls 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. 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. Robust imaging-guided transcriptomics by using meta-analytic imaging results to guide independent postmortem 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. Our findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provide novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.