TY - JOUR
T1 - Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes
AU - Arasappan, Dhivya
AU - Eickhoff, Simon B.
AU - Nemeroff, Charles B.
AU - Hofmann, Hans A.
AU - Jabbi, Mbemba
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - Behavior
KW - Brain
KW - Gene expression
KW - Mood disorders
KW - RNA-sequencing
KW - Transcription factors
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U2 - 10.1007/s12035-020-02195-8
DO - 10.1007/s12035-020-02195-8
M3 - Article
C2 - 33411239
AN - SCOPUS:85099111576
VL - 58
SP - 1978
EP - 1989
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 5
ER -