Candidate pharmacological treatments for substance use disorder and suicide identified by gene co-expression network-based drug repositioning.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Sex differences in brain gene expression among suicide completers.

BACKGROUND: Suicide rates vary substantially by sex. Suicides committed by males significantly outnumber female suicides. Disparities in community and social factors provide a partial explanation for this phenomenon. Thus, the evaluation of sex differences at a biological level might contribute to the elucidation of the factors involved in this imbalance. The aim of the present study was to evaluate sex-specific gene expression patterns in the suicidal brain. METHODS: postmortem samples from the dorsolateral prefrontal cortex (DLPFC) of 75 Latino individuals were analyzed. We considered the following groups: i) male suicides (n = 38), ii) female suicides (n = 10), iii) male controls (n = 20), and iv) female controls (n = 7). Gene expression profiles were evaluated by microarrays. Differentially expressed genes among the groups were identified with a linear model. Similarities and differences in the gene sets between the sexes were identified. RESULTS: Differentially expressed genes were identified between suicides and controls of each sex: 1,729 genes in females and 1,997 genes in males. Female-exclusive suicide genes were related to cell proliferation and immune response. Meanwhile, male-exclusive suicide genes were associated to DNA binding and ribonucleic protein complex. Sex-independent suicide genes showed enrichment in mitochondrial and vesicular functions. LIMITATIONS: Relatively small sample size. Our diagnosis approach was limited to information found on coroner's records. The analysis was limited to a single brain area (DLPFC) and we used microarrays. CONCLUSION: Previously unexplored sex differences in the brain gene expression of suicide completers were identified, providing valuable foundation for the evaluation of sex-specific factors in suicide.

Brain Gene Expression Profiling of Individuals With Dual Diagnosis Who Died by Suicide.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

BACKGROUND/AIM: Although individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies. METHODS: We evaluated the gene expression profile in the dorsolateral prefrontal area of suicides and nonsuicides with and without SUD by microarrays. RESULTS: We identified 222 differentially expressed genes, predominately enriched in cell proliferation in the comparison between suicides with and without SUD. When comparing the transcriptome of suicides with SUD to nonsuicides with SUD, we identified 550 differentially expressed genes, mainly enriched in oxidative phosphorylation. Differentially expressed genes (1,417) between suicides and nonsuicides without SUD were detected. Most of them were related to mitochondrial function. CONCLUSION: Interaction between suicide and SUD seems to influence the expression of genes involved in glial proliferation and glutamatergic neurotransmission. These results highlight, for the first time, that suicides with SUD have a gene expression profile distinct from that of subjects with only one of these disorders.

SFRP1 repression in prostate cancer is triggered by two different epigenetic mechanisms.

Worldwide, prostate cancer (PCa) is the second cause of death from malignant tumors among men. Establishment of aberrant epigenetic modifications, such as histone post-translational modifications (PTMs) and DNA methylation (DNAme) produce alterations of gene expression that are common in PCa. Genes of the SFRP family are tumor suppressor genes that are frequently silenced by DNA hypermethylation in many cancer types. The SFRP family is composed of 5 members (SFRP1-5) that modulate the WNT pathway, which is aberrantly activated in PCa. The expression of SFRP genes in PCa and their regulation by DNAme has been controversial. Our objective was to determine the gene expression pattern of the SFRP family in prostatic cell lines and fresh frozen tissues from normal prostates (NP), benign prostatic hyperplasia (BPH) and prostate cancer (PCa), by qRT-PCR, and their DNAme status by MSP and bisulfite sequencing. In prostatic cancer cell lines, the 5 SFRPs showed significantly decreased expression levels compared to a control normal prostatic cell line (p<0.0001). In agreement, SFRP1 and SFRP5 genes showed decreased expression levels in CaP fresh frozen tissues compared to NP (p<0.01), while a similar trend was observed for SFRP2. Conversely, increased levels of SFRP4 expression were found in PCa compared to BPH (p<0.01). Moreover, SFRP2, SFRP3, and SFRP5 showed DNA hypermethylation in PCa cell lines. Interestingly, we observed DNA hypermethylation at the promoter of SFRP1 in the PC3 cell line, but not in LNCaP. However, in the LNCaP cell line we found an aberrant gain of the repressive histone posttranslational modification Histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, decreased expression by DNA hypermethylation of SFRP5 is a common feature of PCa, while decreased expression of SFRP1 can be due to DNA hypermethylation, but sometimes an aberrant gain of the histone mark H3K27me3 is observed instead.