Abstract
Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.
Highlights
Schizophrenia (SZ) is a complex disorder with highly variable clinical manifestations of psychotic symptoms, such as auditory hallucinations, paranoid or bizarre delusions, disorganized thinking, and significant social dysfunction
To evaluate the roles of rare H3K4me[3] variations, we searched for loci with significant individual alterations in patients with SZ with at least 1.5-fold changes in particular SZ individual compared to all control individuals (Fig. 1) to focus on the most robust individual epigenetic variants
We found nominally significant overlap of epigenetic up- or downregulated H3K4me[3] loci and loci harboring SNPs with suggestive associations (GWAS P < 1 × 10–6) with major depression disorder (MDD) in the GDG set for the SZ14 (P = 0.04) groups (Supplementary Table 11)
Summary
Schizophrenia (SZ) is a complex disorder with highly variable clinical manifestations of psychotic symptoms, such as auditory hallucinations, paranoid or bizarre delusions, disorganized thinking, and significant social dysfunction. Higher concordance in monozygotic twins than in dizygotic twins or siblings indicates that there is a genetic component to this disease. The genetic methods, such as linkage in pedigrees and large scale genome-wide association studies (GWASs) have. The human genome is decorated by numerous chemical modifications, jointly referred as “epigenetics” They include direct modifications of DNA bases (for example, methylation of cytosines) and changes of histones, which form a nucleosome—a protein complex DNA wraps around. Both of these epigenetic modifications are connected to gene expression[8,9]. Epigenetics may at least partly explain the unexplained proportion of SZ genetic component
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