Abstract
BackgroundThe importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls.ResultsThe methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder.ConclusionsOur results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.
Highlights
The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking
We provide the first detailed interrogation of DNA methylation differences between neurons and oligodendrocytes and between brain tissues from patients with schizophrenia compared to controls
These data demonstrate an extensive epigenetic distinction between two major cell types in the brain and that cell type-specific methylation is dysregulated in a specific way in the brains from patients with schizophrenia
Summary
The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. Many of the schizophrenia risk loci are located in the non-coding regions of the genome, suggesting gene regulation plays a role in disease pathology. A large number of these risk loci are associated with alterations in the gene expression in schizophrenia [2, 5, 6]. These observations implicate epigenetic mechanisms as potential mediators of genetic risk. Genome-wide analyses of DNA methylation are revealing that variation in DNA methylation outside of promoters and CpG islands define the critical epigenetic difference between diverse cell types
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