Abstract
Suicide rates have increased steadily world-wide over the past two decades, constituting a serious public health crisis that creates a significant burden to affected families and the society as a whole. Suicidal behavior involves a multi-factorial etiology, including psychological, social and biological factors. Since the molecular neural mechanisms of suicide remain vastly uncharacterized, we examined transcriptional- and methylation profiles of postmortem brain tissue from subjects who died from suicide as well as their neurotypical healthy controls. We analyzed temporal pole tissue from 61 subjects, largely free from antidepressant and antipsychotic medication, using RNA-sequencing and DNA-methylation profiling using an array that targets over 850,000 CpG sites. Expression of NPAS4, a key regulator of inflammation and neuroprotection, was significantly downregulated in the suicide decedent group. Moreover, we identified a total of 40 differentially methylated regions in the suicide decedent group, map** to seven genes with inflammatory function. There was a significant association between NPAS4 DNA methylation and NPAS4 expression in the control group that was absent in the suicide decedent group, confirming its dysregulation. NPAS4 expression was significantly associated with the expression of multiple inflammatory factors in the brain tissue. Overall, gene sets and pathways closely linked to inflammation were significantly upregulated, while specific pathways linked to neuronal development were suppressed in the suicide decedent group. Excitotoxicity as well as suppressed oligodendrocyte function were also implicated in the suicide decedents. In summary, we have identified central nervous system inflammatory mechanisms that may be active during suicidal behavior, along with oligodendrocyte dysfunction and altered glutamate neurotransmission. In these processes, NPAS4 might be a master regulator, warranting further studies to validate its role as a potential biomarker or therapeutic target in suicidality.
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Introduction
Suicide is a leading cause of death, with more than 700,000 cases registered across the globe each year [1]. Suicide tragically affects all age groups, including adolescents, pregnant and post-partum women, as well as elderly individuals. It is the most common cause of death due to non-accidents for people below the age of 35 years [2]. Mood disorders such as major depressive disorder (MDD) are commonly associated with suicide [3], with as many as 60% of those who die by suicide having had a diagnosis of MDD [4]. MDD has an elevated rate of both suicidal ideation, and nonfatal and fatal suicide attempts [66]. Interestingly, HSPA1B and HSPA1A were ranked 60 and 53 by the lowest P-value in our DE gene list, while GNAS was a differentially methylated gene in our suicide decedent group. Moreover, estrogen signaling was also close to significant in our transcriptome enrichment analysis (KEGG pathway analysis, FDR = 0.053).
As our next step, we performed an enrichment analysis, which showed that several gene sets and pathways related to inflammation, infection, and neuronal development were both differentially expressed and methylated in the suicide decedents. Overall, the suicide decedent group showed an activation of gene sets related to inflammation and excitotoxic mechanisms, accompanied by a suppression of gene sets related to maturation of OLs and myelination. The deconvolution analysis indicated an increased ratio of inhibitory neurons against excitatory neurons in the suicide decedent group and further an imbalance in several neurotransmitters, as illustrated in Supplementary Fig. 1. The balance of inhibitory and excitatory neurotransmitter levels plays a significant role in several psychiatric disorders including MDD [67, 68]. Interestingly, the concentration of these neurotransmitters might not only be associated with the numbers of their interneurons but also with their functions [69, 70].
Moreover, utilizing deconvolution analysis, we found that the suicide decedent group had fewer OLs than the healthy control group in all reference brain regions. In line with this, Aston and colleagues have previously reported abnormalities of oligodendroglia in the temporal pole from patients with MDD by transcriptome analysis [71]. Our enrichment analysis demonstrated that the suicide decedent group exhibited suppression of a gene set that was also found to be down regulated in Aston’s study in MDD (Fig. 2A). Our enrichment analysis identified 10 gene sets and pathways that relate to OLs development and myelination process. Genes encoding the key myelination-related proteins Myelin Basic Protein (MBP) and Myelin Associated Oligodendrocyte Basic protein (MOBP) ranked 11th and 25th in our DE gene list. Consistent with our findings, previous transcriptome analyses of suicide postmortem frontal cortex tissue found a lower expression of genes involved in OLs differentiation [19] and a reduction of OPCs in subjects who died from a violent suicide compared to a non-violent suicide [64]. We also found the gene ZNF24 to be significantly hypermethylated in the suicide decedent group. ZNF24 (also known as ZFP24, ZFP191) is a transcriptional regulator, and phosphorylation of ZNF24 controls the developmental process of oligodendrocyte progenitor cells to pre-myelinating OLs [72] and as such it is required by OLs during myelination [73]. We detected that almost all the ZNF24 CpGs were located in the promotor region and hypermethylated in the suicide decedent group, consistent with suppression of gene expression [74].
Previous studies have shown that OLs and their precursors are vulnerable to inflammation, oxidative stress and elevated glutamate levels [75], which explains why these cells are affected in multiple neuropathological entities, including Alzheimer’s disease, spinal cord injury, Parkinson’s disease, and ischemia, as well as during hypoxia [76, 77]. OL deficits have also been previously reported in schizophrenia and bipolar disorder [78, 79] and direct evidence of altered oxidative stress markers has been detected in OLs from MDD suicide postmortem brain tissues [80]. The coincidence of gene expression patterns between upregulation of immune response and down regulation of maturation of OLs in suicide decedents in our study might suggest a causal relationship between the two. Indeed, OPCs were shown to be cytotoxic targets of neuroinflammation in a study of the demyelinating disease multiple sclerosis [81]. Also, there is experimental evidence that OLs block their own differentiation in response to inflammation by activating toll-like receptor-3 (TLR3) [82]. Deconvolution analysis heavily relies on the reference datasets used. While we utilized a widely cited single-cell sequencing dataset from the human brain [44], it is worth noting that the brain regions in this dataset do not precisely align with Brodmann Area 20, as we were unable to find a single-cell dataset specific only to this region. However, in the regions utilized for deconvolution, there is a partial overlap with Brodmann Area 20, and we were able to identify a consistent pattern of lower oligodendrocyte cell populations in the suicide decedent group compared to the control group. To further validate our findings and address the regional specificity, conducting future single-cell RNA sequencing specifically from Brodmann Area 20 would be valuable.
Another recent integrative DNA methylation (via Infinium human 450 BeadChip) and gene expression analysis (via Illumina HumanHT-12 V4 Expression BeadChip) on postmortem brain tissue from male suicide decedents identified 622 differentially expressed genes in the suicide decedent group compared with controls [83]. Among them, 70 genes had concordant methylation and expression changes including genes relevant to psychiatric disorders such as ADCY9, CRH, NFATC4. None of these genes were differentially expressed or methylated in our study. That study differs from our current one in that more than half of the subjects in the previous study had a history of substance abuse, and many, including the controls, had a variety of psychiatric disorders [83]. In contrast, the suicide decedents in our study were largely free from psychotrophic medication, as confirmed with postmortem toxicology, and had a confirmed diagnosis of MDD. The region of analysis, the prefrontal cortex, was also different from our current study as we utilized tissue from the temporal pole, another region proposed to be involved in suicidal behavior [84, 85]. We have previously conducted a pilot study analyzing prefrontal cortical tissue and found evidence of both hypermethylation and a focus of findings in inflammation and neurotrophic pathways [86, 87].
Limitations of this study
Our DNA methylation analysis used Illumina EPIC array platform which is designed to cover 30% of the human methylome [88]. Thus, inferences made from these methylation profiles require cautious interpretation. Moreover, our DNA methylation analysis only detects the CpG sites while it has been shown that non-CpG methylation can also play a role in both neurons and glial cells [89], especially later in life [90]. Furthermore, our sample sizes are relatively small for the Illumina Epic 850k array, so it is likely that we have missed additional differentially methylated regions [91]. Another limitation is the dissection process of the brain tissue, which can lead to slight variation in the anatomical region used for analysis. Since the dissected brain gyri fold in three dimensions, it is impossible to exclude all white matter while still taking the full thickness (~ 3 mm) of the cortical ribbon. However, it is important to note that any random variation during dissection should not impact the groups differently, as pathologists were blind to future study design and analytical approaches. Despite the limitations of this study, it is important to note that the data presented here offer important indications of distinct molecular signatures in well-characterized suicidal individuals, without any major influence of psychotrophic medication, and that they can serve as the basis for designing future targeted studies.
Conclusions
Overall, our study suggests a network of mechanisms involved in suicidal behavior, centering on upregulated inflammatory pathways and the suppression of oligodendrocyte-related genes. It is plausible to propose that in the brain, NPAS4 may serve as a master transcriptional regulator that modulates neural and neuronal circuit development while maintaining mitochondrial and immune function. NPAS4 downregulation could lead to excitatory and inhibitory imbalance, impaired neural development, increased oxidative stress and neuroinflammation. Our results confirm the involvement of inflammatory pathways in active suicidal behavior and suggest that NPAS4-associated mechanisms might serve as novel targets in the development of therapies for suicide prevention. Further, this work also supports that the role of OLs should be further evaluated in suicidal behavior.
Code availability
The codes used in this project can be found at https://github.com/psychesha21/RNAseq_Analysis and https://github.com/psychesha21/DNA-methylation. Sequencing data for RNA and DNA methylation can be accessed by GEO accession number: SuperSeries GSE243488.
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Acknowledgements
The study was funded by the National Institutes of Mental Health (NIMH R01 MH118211-01A1) awarded to the multi-PI team of LB, JJM and EDA. We wish to thank all the families of the deceased participants for their donation of brain tissue, as well as the sharing of detailed clinical information by participating in our interviews. Moreover, we wish to thank the genomics core at Van Andel Institute, headed by Ms. Marie Adams, for their work on the RNA-sequencing analysis.
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LB, JJM and EDA jointly planned the experiments and led the analysis and interpretation of the data, as well as manuscript writing. QS performed the statistical and bioinformatical analysis of the data and drafted the first version of the manuscript. ZF contributed to the bioinformatical analysis and manuscript writing. MLEG provided advice on the experimental plan and assisted in manuscript writing, ZM provided statistical advice. JAS assisted with manuscript writing, IRB related paperwork and project logistics. HG provided statistical advice and assisted in manuscript writing. AD, GR, MDU and NS all contributed with gathering clinical information from psychological autopsies as well as neuropathological examinations and assisted with manuscript writing. All authors have contributed to, and approved of the final version of the manuscript.
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EDA receives grants or contracts from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, Karuna, Lundbeck, National Network of Depression Centers, Neurocrine Biosciences, Otsuka, Pear Therapeutics, Takeda, Teva. He receives consulting fees from: Alkermes, Atheneum, CAPNOS Zero (unpaid), Indivior, Karuna, Lundbeck, Otsuka, Neurocrine Biosciences, Sunovion, Teva. He receives payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Otsuka/Lundbeck. He receives support for attending meetings and/or travel from Alkermes, Karuna, Otsuka/Lundbeck, Neurocrine Biosciences. Stock or stock options: AstraZeneca, Johnson and Johnson, Moderna, Pfizer. AJD receives funding from NIMH (R0112530) and the Bay Area Lyme Biobank. HG and her family own stocks in Ilumina, Inc. JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. Other co-authors have no competing interest.
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Sha, Q., Fu, Z., Escobar Galvis, M.L. et al. Integrative transcriptome- and DNA methylation analysis of brain tissue from the temporal pole in suicide decedents and their controls. Mol Psychiatry 29, 134–145 (2024). https://doi.org/10.1038/s41380-023-02311-9
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DOI: https://doi.org/10.1038/s41380-023-02311-9
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