@article {Jabbi864900, author = {Mbemba Jabbi and Dhivya Arasappan and Simon B. Eickhoff and Hans A. Hofmann}, title = {Transcription factor motifs in anterior insula gene-expression in mood disorder}, elocation-id = {864900}, year = {2019}, doi = {10.1101/864900}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Background Organizational principles of brain structure and function are important for mediation of complex adaptive behavioral traits. When aspects of these hierarchical brain organizations go awry, maladaptive disease phenotypes with varying behavioral implications emerge. The hierarchical organizations of the neurobiological blueprints for adaptive behavior are governed by the role of genes, especially their expressive codes, in mediating molecular processes critical for the cellular and systems-level development and functions of the brain, which, in turn bridges the genetic effects on complex behavioral phenotypes. Although over ~10\% of the United States adult population suffers from mood-related symptoms and disability, hierarchical gene expression modules underlying pathological brain phenotypes associated with diagnostic mood symptoms remains poorly undefined.Methods Here, we dissected anterior insula tissue identified to be reduced in volume in mood disorders and extracted RNA-samples from the dissected tissue in an independent postmortem mood disorder and unaffected control samples. We then performed RNA-sequencing with the RNA-samples to identify differentially expressed genes (DEGs) in lifetime diagnoses of a) bipolar disorder (BD; n=37), b) major depressive disorder (MDD; n=30) vs and c) non-psychiatric controls (n=33). Given the role of transcription factors (TFs) in regulating gene expression via specific DNA-binding domains (motifs) in the gene promoters, we followed-up on our previous study (Jabbi et al. submitted) that identified whole transcriptome gene expression profiles in mood disorders, with the aim to explore in more detail, the regulatory logic of mood disorder transcriptomics by identifying TF motifs involved in regulating the previously identified mood disorder related gene expression landscape. To this goal, we used JASPAR TF binding database to identify motifs for DEGs in BD vs controls; MDD vs controls, and in a pooled cohort of BD \& MDD individuals with high Axis-I comorbidity vs low Axis-I comorbidity.Results We found that differential gene expressions (DEGs) in BD vs controls were enriched with motifs of REL, MIR210, SMADD3, TEAD4, HINFP, AP1, NFE2, IRF9, RUNX2, and FOXA3 TFs. DEGs in MDD vs controls were found to be enriched with motifs of SPI1, IRF9, LTF, FOS, FOXO3A, SND1, PPARA, MIR138, and CBEPA TFs. Of interest, DEGs profiles for Axis-I comorbidity load which was factor analytically clustering with suicide mortality in the pooled BD \& MDD postmortem donor samples (i.e. without control donors included in the analysis) were found to be enriched with motifs of NFATC2, GABPA, HMAGA1, NR3C1, GTF2i, IRF2, POU1F1, SAMD9L, SNAI1, and CBEPB TFs. Collectively, these TFs are known to regulate expression of toll-like receptor signaling genes, cellular homeostatic control genes, and genes involved in embryonic, cellular and neurodevelopmental processes.Conclusion Recent genomic advances are transforming our understanding of the molecular building blocks of complex behavioral phenotypes including mood disorders. Here, we applied robust image-guided transcriptomics by first targeting the most pronounced gray matter loss in the anterior insula underlying mood disorder diagnoses, to guide an independent postmortem RNA-seq study of TF motifs regulating gene-expression enrichments in mood disorders. We identified TF motifs for differentially expressed innate-immune, cellular homeostasis, embryonic and neurodevelopmental processes. Together, our results provide the foundation for better understanding of the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate neuroanatomical abnormalities underlying behavioral dysfunctions.}, URL = {https://www.biorxiv.org/content/early/2019/12/05/864900}, eprint = {https://www.biorxiv.org/content/early/2019/12/05/864900.full.pdf}, journal = {bioRxiv} }