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

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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 of mood 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.

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Acknowledgments

The NIMH Human Brain Collection Core provided RNA samples for donors and we thank the NIMH and Drs. Barbara Lipska, Stefano Marenco, Pavan Auluck, and HBCC colleagues for the studied samples. We thank Wade Weber of Dell Medical School Psychiatry Department, UT Austin, for assistance in preparing the manuscript, Dr. Mark Bond of Dell Medical School Psychiatry Department, UT Austin, for statistical reviews, and Jessica Podnar and several GSAF colleagues for RNA-seq support.

Funding

This work was supported by the Dell Medical School, UT Austin Mulva Neuroscience Clinics Startup funds for MJ; DA and CBN are supported by the National Institutes of Health (NIH) and HH is supported by NSF.

The funding bodies nor any other entities were involved in the design of the study and collection, analysis, and interpretation of data presented here.

Author information

Authors and Affiliations

Authors

Contributions

MJ conceived and designed the studies, and acquired postmortem material from the NIMH HBCC. DA, SBE, and MJ performed the experiments and analyzed the data and results. DA and MJ drafted the manuscript and SBE, CBN, and HH contributed critically and substantially to the content of the manuscript.

Corresponding author

Correspondence to Mbemba Jabbi.

Ethics declarations

The NIMH Human Brain Collection Core (HBCC) provided the Postmortem samples for which informed consent was acquired according to NIH institutional ethical review board (IRB) guidelines and clinical characterization, neuropathology screening, and toxicology analyses followed previous protocols [20]. In addition, the study received a human subject exemption from the University of Texas at Austin IRB given the anonymized nature of postmortem donor sample data that the research team received from the NIH.

Conflict of Interest

Dhivya Arasappan, none; Simon Eickhoff none; Hans Hofmann, none; Mbemba Jabbi, none.

Charles B Nemeroff:

Research/Grants: National Institutes of Health (NIH)

Consulting (last year): Taisho Pharmaceutical, Inc., Signant Health, Sunovion Pharmaceuticals, Inc., Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Acadia Pharmaceuticals, Axsome, Sage, BioXcel Therapeutics, Silo Pharma, Aditum Bio

Stockholder: Xhale, Seattle Genetics, Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, EMA Wellness

Scientific Advisory Boards: Brain and Behavior Research Foundation (BBRF), Anxiety Disorders Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Magnolia CNS

Board of Directors: Gratitude America, ADAA, Xhale Smart, Inc.

Income sources or equity of $10,000 or more: American Psychiatric Publishing, Xhale, Signant Health, CME Outfitters, Takeda, Intra-Cellular Therapies, Inc., EMA Wellness

Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1)

Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2)

Speakers Bureau: None

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Supplementary Table 2-4 Legend. Abbreviations: baseMean, normalized read counts of all samples; log2Foldchange, effect size estimate; lfcSE, standard error of the log2foldchange; stat, Wald statistical test values; pvalue, uncorrected p-value; p-adj, corrected p-value. Fold change is calculated as the ratio of mean expression in high psychiatric morbidity & suicide mortality score to the mean expression in low psychiatric morbidity & suicide mortality score. (DOCX 596 kb)

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Arasappan, D., Eickhoff, S.B., Nemeroff, C.B. et al. Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes. Mol Neurobiol 58, 1978–1989 (2021). https://doi.org/10.1007/s12035-020-02195-8

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