Whole transcriptome RNA-seq of undiseased human prefrontal cortex
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ABSTRACT: We report the application of high-throughput RNA sequencing to the human prefrontal cortex. The brain dataset was obtained by sequencing total RNAs extracted from the dorsolateral prefrontal cortex of five deceased human patients with no apparent pathology, followed by depletion of ribosomal RNA to obtain all non-rRNA coding and non-coding RNAs in the human brain transcriptome. Five samples were sequenced, four coming from frozen brain tissue (frontal cortex) of deceased female human patients with no remarkable pathology, and one from a male patient with no remarkable pathology.
Project description:We report the application of high-throughput RNA sequencing to the human prefrontal cortex. The brain dataset was obtained by sequencing total RNAs extracted from the dorsolateral prefrontal cortex of five deceased human patients with no apparent pathology, followed by depletion of ribosomal RNA to obtain all non-rRNA coding and non-coding RNAs in the human brain transcriptome.
Project description:The surprising observation that virtually the entire human genome is transcribed means we know very little about the function of many emerging classes of RNAs, except their astounding diversity. Traditional RNA function prediction methods rely on sequence or alignment information, which are limited in their ability to classify classes of non-coding RNAs (ncRNAs). To address this, we developed CoRAL, a machine learning-based approach for classification of RNA molecules. CoRAL uses biologically interpretable features including fragment length, cleavage specificity, and antisense transcription to distinguish between different ncRNA classes. We evaluated CoRAL using genome-wide small RNA sequencing (smRNA-seq) datasets from two human tissue types (brain and skin [GSE31037]), and were able to classify six different types of RNA transcripts with 79~80% accuracy in cross-validation experiments, and with 71~73% accuracy when CoRAL uses one tissue type for training and the other as validation. Analysis by CoRAL revealed that long intergenic ncRNAs, small cytoplasmic RNAs, and small nuclear RNAs show more tissue specificity, while microRNAs, small nucleolar, and transposon-derived RNAs are highly discernible and consistent across the two tissue types. The ability to consistently annotate loci across tissue types demonstrates the potential of CoRAL to characterize ncRNAs using smRNA-seq data in less characterized organisms. Four samples were sequenced, each one coming from frozen brain tissue (frontal cortex) of a deceased female human patient with no remarkable pathology.
Project description:We compared the genome-wide patterns of DNA methylation in the brains of humans to those of our closest evolutionary relative, chimpanzees, using base-pair resolution whole-genome methylation maps of the prefrontal cortex. Our data reveal that the prefrontal cortex is the most heavily methylated among the human tissues examined so far. Nevertheless, hundreds of genes exhibit dramatically reduced levels of promoter DNA methylation in the human brain relative to the chimpanzee brain. Many of these genes are associated with neurological disorders, psychological disorders, and cancers, and are enriched for functions related to cellular metabolic processes and protein binding. Moreover, the majority of these genes exhibit higher expression in the human brain compared to the chimpanzee brain. Profiling DNA methylation map in prefrontal cortex regions of postmortem brains of three humans and three chimpanzees
Project description:Alzheimer's disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. We undertook an epigenome-wide association study across three independent brain tissue cohorts (total n = 999) to identify differential DNA methylation associated with neuropathology in the superior temporal gyrus and prefrontal cortex. We present robust evidence for elevated DNA methylation associated with AD neuropathology across an extended region spanning the HOXA gene cluster on chromosome 7. Prefrontal cortex and superior temporal gyrus tissue from 147 individuals with varying levels of AD pathology. DNA modifications for these samples were quantified using the Illumina Infinium Human 450K Methylation Array.
Project description:This SuperSeries is composed of the following subset Series: GSE17757: Gene expression data from primate postnatal brain in prefrontal cortex: time course GSE18012: miRNA expression data from human postnatal brain in prefrontal cortex: time course GSE18013: miRNA expression data from rhesus macaque postnatal brain in prefrontal cortex: time course Refer to individual Series
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.
Project description:Background: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development, and there is mounting evidence to support a role for developmentally-regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. Results: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that disease-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. Conclusions: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects. 33 post-mortem brain (prefrontal cortex) samples (18 schizophrenia cases and 15 controls) were obtained from Douglas Bell-Canada Brain Bank (DBCBB), Montreal, Canada. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.
Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. The major human specific genes in prefrontal cortex was enriched in neuronal functions and regulated by several transcription factors, which were previously implicated in regulation of neuronal functions. To confirm neuronal function of the human prefrontal cortex specific genes, we identifed response genes upon neuronal activation in mouse cortical neurons. Our results show that human specific genes are enriched in the response genes upon neuronal activation, implying the function of human prefrontal cortex specific genes in synaptic development. The cortical neurons from E15 mouse were isolated and cultured. We then exposed neurons to bicuculline (Bic), or potassium chloride (KCl), or without treatment. The cultured neurons under each group were hybridized to Agilent whole mouse genome oligo microarray (4x44k).
Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. The major human specific genes in prefrontal cortex was enriched in neuronal functions and regulated by several transcription factors, which were previously implicated in regulation of neuronal functions. To confirm neuronal function of the human prefrontal cortex specific genes, we identifed response genes upon neuronal activation in mouse cortical neurons. Our results show that human specific genes are enriched in the response genes upon neuronal activation, implying the function of human prefrontal cortex specific genes in synaptic development.