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Cited by 38Polyamine Metabolism and ApplicationsTreatment of Major DepressionSuicide and Self-Harm Studies

Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 ( SAT1 ) gene in major depression and suicide

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Pantazatos, Spiro P., Andrews, Stuart J., Dunning-Broadbent, Jane, Pang, Jiuhong, Huang, Yung-yu, Arango, Victoria, Nagy, Peter L., John Mann, J.·2015·Neurobiology of Disease
DOI 10.1016/j.nbd.2015.04.014PMC PMC4834874
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Abstract

Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N = 29), DSM-IV major depressive disorder suicides (MDD-S, N = 21) and MDD non-suicides (MDD, N = 9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p = 0.002) and MDD (vs. HC, p = 0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) were pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p < 0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expressions of both SSAT and SATX isoforms suggest that shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide.

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  • Combining GWAS with transcriptome data indicates that suicide-related genes are associated with inflammation, the HPA axis, GABA and glutamate neurotransmission, and neurogenesis.

    “Combining GWASs with transcriptome data indicates that suicide-related genes are associated with inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, γ-aminobutyric acid (GABA) and glutamate neurotransmission, and neurogenesis (51-56).”

    From A brain-centric model of suicidal behavior (2020) · cites this paper as [53]

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Authors
Pantazatos, S. P., Andrews, S. J., Dunning-Broadbent, J., Pang, J., Huang, Y.-Y., Arango, V., Nagy, P. L., & John Mann, J.
Affiliations
  • New York State Psychiatric Institute (US)
  • Columbia University (US)
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2015-07
Volume
79
Pages
123-134
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2015.04.014
PMC
PMC4834874
OpenAlex
W1546729188
Cited by
38
References
57
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 1 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 1 · 2014: 1
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NIMH (MH082041)
  • Paul Janssen Translational Neuroscience Postdoctoral Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
Keywords
SAT1, spermidine/spermine N1-acetyltransferase, major depressive disorder, suicide, polyamine catabolism, gene isoforms, SSAT, alternative splicing, dorsolateral prefrontal cortex, postmortem brain, microRNA, gene expression profiling
MeSH terms
Diamine N-Acetyltransferase, Acetyltransferases, Adult, Major Depressive Disorder, Exons, Female, Humans, Male, Middle Aged, Suicide, Linear Models, Prefrontal Cortex, Alternative Splicing, Gene Expression Profiling, MicroRNAs, Transcriptome

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