Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers
Abstract
CONTEXT: Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor-TrkB signaling has been linked to mood disorders. OBJECTIVE: To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process. DESIGN: Postmortem case-control study. Patients, Setting, and MAIN OUTCOME MEASURES: Thirty-nine French Canadian men underwent screening at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a microarray screening approach for extreme expression differences across subjects and a conventional screening approach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal experiments were performed to control for drug and alcohol effects. Genetic and epigenetic studies were performed by means of direct sequencing and bisulfite mapping. RESULTS: We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduction in astrocyte number. We found no effect of genetic variation in a 2500-base pair promoter region or at relevant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression. CONCLUSION: A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region.
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Fluorescence-activated cell sorting techniques and single-cell epigenomics can facilitate the examination of DNA methylation in various cell types.
“Fluorescence-activated cell sorting techniques and single-cell epigenomics can facilitate the examination of DNA methylation various cell types.106,411”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [411]
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- Authors
- Ernst, C., Deleva, V., Deng, X., Sequeira, A., Pomarenski, A., Klempan, T., Ernst, N., Quirion, R., Gratton, A., Szyf, M., & Turecki, G.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2009-01-01
- Volume
- 66
- Issue
- 1
- Pages
- 22
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2055113972
- Cited by
- 235
- References
- 72
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 13 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 9 · 2018: 11 · 2017: 11 · 2016: 16 · 2015: 15 · 2014: 24 · 2013: 17 · 2012: 19
- FWCI
- 25.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- TrkB.T1, suicide, frontal cortex, alternative splicing, DNA methylation, promoter methylation, astrocytes, epigenetics, gene expression, mood disorders, postmortem brain
- MeSH terms
- Alleles, Astrocytes, Cerebellum, Frontal Lobe, Humans, Male, Promoter Regions, Genetic, Suicide, Blotting, Western, Polymerase Chain Reaction, Alternative Splicing, DNA Methylation, Protein Isoforms, Oligonucleotide Array Sequence Analysis, Receptor, trkB, Gene Expression Profiling, Epigenesis, Genetic
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