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Neuronal brain region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability [ATAC-Seq]

ABSTRACT: We analyzed differential methylation (via WGBS) between four distinct human brain regions (NAcc-nucleus accumbens, BA9-dorsolateral prefrontal cortex, BA24-anterior cingulate cortex, and HC-hippocampus) in both sorted nuclei and intact tissues. We isolated neuronal and non-neuronal (glial) nuclei from the same six individuals for each tissue via FACS using the neuronal marker, NeuN. Additionally, we performed WGBS from non-sorted tissues from these same brain regions in a total of 12 individuals (BA9 n = 9; BA24 n = 5; HC n = 6; NAcc n = 7). To complement our DNA methylation analyses, we measured gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) in neuronal and non-neuronal nuclei from the nucleus accumbens and dorsolateral prefrontal cortex from six more individuals. We then performed an integrative analysis to understand how the epigenome contributes to brain region-specific function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96614 | GEO | 2018/12/17

REPOSITORIES: GEO

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Project description:Schizophrenia (SZ) and bipolar disorder (BD) are severe neuropsychiatric disorders with serious impact on patients, together termed major psychosis. Recently, long intergenic non-coding RNAs (lincRNAs) were reported to play important roles in mental diseases. However, little was known about their molecular mechanism in pathogenesis of SZ and BD. Here, we performed RNA sequencing on 82 post-mortem brain tissues from three brain regions (orbitofrontal cortex (BA11), anterior cingulate cortex (BA24) and dorsolateral prefrontal cortex (BA9)) of patients with SZ and BD and control subjects, generating over one billion reads. We characterized lincRNA transcriptome in the three brain regions and identified 20 differentially expressed lincRNAs (DELincRNAs) in BA11 for BD, 34 and 1 in BA24 and BA9 for SZ, respectively. Our results showed that these DELincRNAs exhibited brain region-specific patterns. Applying weighted gene co-expression network analysis, we revealed that DELincRNAs together with other genes can function as modules to perform different functions in different brain regions, such as immune system development in BA24 and oligodendrocyte differentiation in BA9. Additionally, we found that DNA methylation alteration could partly explain the dysregulation of lincRNAs, some of which could function as enhancers in the pathogenesis of major psychosis. Together, we performed systematical characterization of dysfunctional lincRNAs in multiple brain regions of major psychosis, which provided a valuable resource to understand their roles in SZ and BD pathology and helped to discover novel biomarkers. RNA sequencing of 82 brain samples including each of 19 from BA9 and BA24 and 44 from BA11. We performed RNA sequencing on three brain regions namely the BA11 (part of orbitofrontal cortex), BA24 (part of anterior cingulate) and BA9 (part of dorsolateral prefrontal cortex) from SZ and BD patients and psychiatrically normal individuals.In summary, there were 44 BA11 samples from 16 SZ, 16 BD and 12 control subjects, and 19 BA24 and 19 BA9 samples from the same subjects including 6 SZ, 7 BD and 6 controls.

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Neuronal brain region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability [ATAC-Seq]

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