Project description:Purpose: The goal of this study to examine mRNA transcriptomic changes in reward-related brain regions of subjects with alcohol use disorder. Methods: Total RNAs were extracted from postmortem caudate nucleus of 12 AUD and 12 control subjects. rRNA depletion RNA sequencing was performed and the sequence reads were processed using the bulk RNA-seq processing pipeline Pipeliner workflow (Federico et al. Front Genet 2019; 10, 614). AUD-associated mRNA transcriptomic changes were analyzed by the Limma-Voom method. Results: Differentially expressed mRNAs (absolute FC>2.0 & P<0.05) were identified in postmortem caudate nucleus of subjects with alcohol use disorder (AUD). Chronic alcohol consumption may alter mRNA transcriptome profiles in reward-related brain regions, resulting in alcohol-induced neuroadaptations.
Project description:Schizophrenia-associated anomalies in gene expression in postmortem brain are caused by a combination of genetic and environmental influences. Given the small effect size of common variants it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. However, at the gene level we will see more impact from common environmental risk factors mediated by influential epigenomic modifiers. In this study we examine changes in cortical gene expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n=74 matched pairs of schizophrenia, schizoaffective and control samples) was performed using Illumina HT12 gene expression microarrays. Significant gene interaction networks were identified for differentially expressed genes in pathways of neurodevelopmental and oligodendrocyte function.
Project description:Post mortem human brain tissue comparison between HD patients and controls from 3 brain regions - cerebellum, frontal cortex [BA4, BA9] and caudate nucleus. Gene expression analysed using linear models from LIMMA package in Bioconductor suite. Keywords: disease state analysis
Project description: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.
Project description:Post mortem human brain tissue comparison between HD patients and controls from 3 brain regions - cerebellum, frontal cortex [BA4, BA9] and caudate nucleus. Gene expression analysed using linear models from LIMMA package in Bioconductor suite. Experiment Overall Design: Large sample sizes were used to examine brain tissue gene expression at various stages of HD pathology. Three brain regions were profiled, compared and analysed for differential gene expression. The broad aim was to capture early stage gene expression changes in HD brains.