Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes
- 7 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Neurobiology
- Vol. 58 (5), 1978-1989
- https://doi.org/10.1007/s12035-020-02195-8
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.Keywords
Funding Information
- National Institute of Mental Health
- National Science Foundation
- Mulva Clinics for the Neurosciences
This publication has 102 references indexed in Scilit:
- Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010The Lancet, 2013
- Decreased expression of synapse-related genes and loss of synapses in major depressive disorderNature Medicine, 2012
- The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and functionProceedings of the National Academy of Sciences of the United States of America, 2012
- Activation likelihood estimation meta-analysis revisitedNeuroImage, 2012
- Grand challenges in global mental healthNature, 2011
- Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studiesMolecular Psychiatry, 2009
- Coordinate‐based activation likelihood estimation meta‐analysis of neuroimaging data: A random‐effects approach based on empirical estimates of spatial uncertaintyHuman Brain Mapping, 2009
- Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic developmentProceedings of the National Academy of Sciences of the United States of America, 2009
- How do you feel — now? The anterior insula and human awarenessNature Reviews Neuroscience, 2009
- Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey ReplicationArchives of General Psychiatry, 2005