Integrative Analyses of scRNA-seq, Bulk mRNA-seq, and DNA Methylation Profiling in Depressed Suicide Brain Tissues

Abstract

Background Suicidal behaviors have become a serious public health concern globally due to the economic and human cost of suicidal behavior to individuals, families, communities, and society. However, the underlying etiology and biological mechanism of suicidal behavior remains poorly understood. Methods We collected different single omic data, including scRNA-seq, bulk mRNA-seq, DNA methylation microarrays from the cortex of MDD with suicide subjects’ studies, as well as fluoxetine-treated rats brains. We matched subject IDs that overlapped between the transcriptome dataset and the methylation dataset. The differential expression genes (DEGs) and differentially methylated regions (DMRs) were calculated with a two-group comparision analysis. Cross-omics analysis was performed to calculate the correlation between the methylated and transcript levels of differentially methylated CpG sites and mapped transcripts. Additionally, we performed a deconvolution analysis for bulk mRNA-seq and DNA methylation profiling with scRNA-seq as the reference profiles. Results The results demonstrated that 17 key genes were finally found to share changes in the different omics and tissues and oligodendrocyte precursor cells (OPCs) have a significant difference in cell type proportions among 7 cell types. Meanwhile, our analysis of single-cell sequence from the antidepressant-treated rats found that drug-specific differential expression genes were enriched into biological pathways, including ion channels and glutamatergic receptors. Conclusions This study identified some important dysregulated genes influenced by DNA methylation in two brain regions of depression and suicide patients. Interestingly, we found that OPCs have the most contributors for cell-type proportions related into differential expression genes and methylated sites in suicidal behavior.

Contrasting genetic predisposition and diagnosis in psychiatric disorders: a multi-omic single-nucleus analysis of the human orbitofrontal cortex

“…Pathways related to neurodegenerative diseases and oxidative phosphorylation showed significant enrichment in both up- and downregulated genes in different cell types. Notably, the Ribosome pathway exhibited significant enrichment, particularly in upregulated genes especially in oligodendrocytes (FDR=5.18×10 -29 ), alongside moderate upregulation observed in OPCs (FDR=7.20×10 -7 ) and endothelial cells (FDR=6.54×10 -11 ). Many pathways enriched in up- and downregulated DE risk genes reflecting genetic risk (Supp.…”

“…Structural and functional abnormalities in areas like the orbitofrontal cortex (OFC), a key component of the ventral prefrontal cortex, have been widely reported in many psychiatric disorders 27 . Brodmann area 11, a subregion of the OFC, has shown reduced grey matter volume in schizophrenia patients 28 and dysregulation of gene expression and DNA methylation in depressed and suicidal patients 29 .…”

Glial Markers of Suicidal Behavior in the Human Brain—A Systematic Review of Postmortem Studies

“…A recent RNA-Seq analysis identified that the transcription of oligodendrocyte cell populations in the temporal cortex (TC) was significantly lower in a depressed suicide group than in psychiatrically normal controls [ 61 ]. In addition, a differentially methylated region analysis of the OFC and ventral anterior cingulate cortex (vACC) from the database indicated significant changes in the cell type proportions of astrocytes, microglia, and oligodendrocytes [ 62 ].…”

“…↓, decreased. →, unchanged [ 34 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”