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Cited by 325MicroRNA in disease regulationTreatment of Major DepressionTryptophan and brain disorders

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MicroRNA Expression Is Down-Regulated and Reorganized in Prefrontal Cortex of Depressed Suicide Subjects

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Smalheiser, Neil R., Lugli, Giovanni, Rizavi, Hooriyah S., Torvik, Vetle I., Turecki, Gustavo, Dwivedi, Yogesh·2012·PLoS ONE
DOI 10.1371/journal.pone.0033201PMC PMC3302855
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Abstract

BACKGROUND: Recent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases. METHODOLOGY/PRINCIPAL FINDINGS: The present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5'-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group. CONCLUSIONS/SIGNIFICANCE: The findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors).

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Crossref · 10.1371/journal.pone.0033201

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Figure 1 Plot of Mean vs standard deviation (SD) for normal control and depressed suicide groups. miRNA expression in the depressed suicide group is significantly less variable than in the control group.
Figure 1 Plot of Mean vs standard deviation (SD) for normal control and depressed suicide groups. miRNA expression in the depressed suicide group is significantly less variable than in the control group.CC BY · PubMed Central
Figure 2 Protein levels of DNMT3b, BCL2, and VEGFA in PFC of depressed suicide (n = 18) and normal control (n = 17) subjects. Protein samples from tissue lysates were subjected to 10% polyacrylamide gel electrophoresis and transferred to enhanced chemiluminescence–nitrocellulose membranes, which were then incubated with primary antibody specific for DNMT3b, BCL2, VEGFA or β-actin and corresponding secondary antibody. The suicide group was compared with the control group. DMNT3b was strongly up-regulated (2.4-fold) in the depressed suicide group (ap = 1×10−11), VEGFA showed no significant change (1.03-fold, bp = 0.4) and BCL2 was strongly down-regulated (0.57 of control, cp = 2.4×10−14). C = Controls; DS = Depressed suicide.
Figure 2 Protein levels of DNMT3b, BCL2, and VEGFA in PFC of depressed suicide (n = 18) and normal control (n = 17) subjects. Protein samples from tissue lysates were subjected to 10% polyacrylamide gel electrophoresis and transferred to enhanced chemiluminescence–nitrocellulose membranes, which were then incubated with primary antibody specific for DNMT3b, BCL2, VEGFA or β-actin and corresponding secondary antibody. The suicide group was compared with the control group. DMNT3b was strongly up-regulated (2.4-fold) in the depressed suicide group (ap = 1×10−11), VEGFA showed no significant change (1.03-fold, bp = 0.4) and BCL2 was strongly down-regulated (0.57 of control, cp = 2.4×10−14). C = Controls; DS = Depressed suicide.CC BY · PubMed Central
Figure 3 Network of microRNAs pairs in normal control and depressed groups. A. Network of microRNA pairs that showed no significant correlation in the normal control group yet did exhibit a significant positive correlation in the depressed suicide group. See text for details. B. Network of microRNA pairs that showed significant positive correlations in the normal control group yet were not correlated in the depressed suicide group. See text for details.
Figure 3 Network of microRNAs pairs in normal control and depressed groups. A. Network of microRNA pairs that showed no significant correlation in the normal control group yet did exhibit a significant positive correlation in the depressed suicide group. See text for details. B. Network of microRNA pairs that showed significant positive correlations in the normal control group yet were not correlated in the depressed suicide group. See text for details.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Y Zhu, 2003, Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression., FASEB J, 17, 186, 10.1096/fj.02-0515com · DOI
  2. DP Bartel, 2009, MicroRNAs: target recognition and regulatory functions., Cell, 136, 215, 10.1016/j.cell.2009.01.002 · DOI · Paper page

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Metadata

Authors
Smalheiser, N. R., Lugli, G., Rizavi, H. S., Torvik, V. I., Turecki, G., & Dwivedi, Y.
Affiliations
  • University of Illinois Chicago (US)
  • University of Illinois Urbana-Champaign (US)
  • McGill University (CA)
Corresponding author
Dwivedi, Yogesh
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-03-09
Volume
7
Issue
3
Pages
e33201
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0033201
PMC
PMC3302855
OpenAlex
W2050613411
Cited by
324
References
58
Citations by year
2026: 5 · 2025: 15 · 2024: 18 · 2023: 19 · 2022: 22 · 2021: 35 · 2020: 24 · 2019: 22 · 2018: 26 · 2017: 30 · 2016: 35 · 2015: 26 · 2014: 20 · 2013: 16 · 2012: 9
FWCI
7.54
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • American Foundation for Suicide Prevention (R21MH081099, MH082802)
  • Stanley Medical Research Institute
  • Canadian Institutes of Health Research (171859_1, 190734_1)
  • National Institute of Mental Health (R21MH081099, R01MH68777, R01MH068777, R01MH082802, MH082802, R21MH091509)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
microRNA expression, depression, suicide, prefrontal cortex, microRNA downregulation, miRNA target genes, chromosomal loci, gene expression regulation
MeSH terms
Adult, Depression, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Proteins, Quebec, Suicide, Blotting, Western, Case-Control Studies, RNA-Binding Proteins, Prefrontal Cortex, DNA Primers, Statistics, Nonparametric, Reverse Transcriptase Polymerase Chain Reaction, MicroRNAs, Ribonuclease III, DEAD-box RNA Helicases, Multiplex Polymerase Chain Reaction

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