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Differential H3K9me2 heterochromatin levels and concordant mRNA expression in postmortem brain tissue of individuals with schizophrenia, bipolar, and controls

ABSTRACT: The existence of repressive and durable chromatin assemblies along gene promoters or networks, especially in the brain, is of theoretical and therapeutic relevance in a subset of individuals diagnosed with schizophrenia who experience a chronic, persistent, and treatment-resistant trajectory. We used chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) to generate an epigenomic map that includes differential sites occupied by di-methylated lysine 9 of histone 3 (H3K9me2), a repressive modification that is yet unexplored in human postmortem brain tissue. We have discovered over 150 significantly differential promoter sites in the postmortem prefrontal cortex tissue of individuals diagnosed with schizophrenia (n=15) when compared to controls (n=15). Potentially dysregulated gene categories include postsynaptic proteins, processing enzymes (for proproteins, lipids, and oxidative stress), cadherin family genes, the complement system, and peptide hormones. Ten genes with significantly increased or decreased H3K9me2 promoter occupation were selected through statistical analysis, function, or previous GWAS association, and qRT-PCR was performed on an extended sample of postmortem brain tissue, adding an additional 17 controls, 7 individuals with schizophrenia, and 19 individuals with bipolar samples (n=32 control, 22 schizophrenia, 19 bipolar). This approach revealed that mRNA expression levels correlated with chromatin modification levels in eight of ten selected genes, and mRNA expression in the total sample could be predicted by the occupancy of H3K9me2. Utilization of this method and replication in a larger sample open a pathway to durable and restrictive epigenomic assemblies whose accumulation across the lifespan of individuals diagnosed with schizophrenia may explain treatment resistance, and advance therapeutic options.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215991 | GEO | 2022/10/25

REPOSITORIES: GEO

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Project description:Genome wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by an exon microarray study. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders. There were 20 anterior cingulate postmortem brain samples that were extracted for total RNA, and analyzed using Affymetrix Exon Array (bipolar disorder subjects n = 9, controls n = 11).

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Differential H3K9me2 heterochromatin levels and concordant mRNA expression in postmortem brain tissue of individuals with schizophrenia, bipolar, and controls

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