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Transcriptomic analysis of postmortem brain identifies dysregulated splicing events in novel candidate genes for schizophrenia.

ABSTRACT: The diverse spatial and temporal expression of alternatively spliced transcript isoforms shapes neurodevelopment and plays a major role in neuronal adaptability. Although alternative splicing is extremely common in the brain, its role in mental illnesses such as schizophrenia has received little attention. To examine this relationship, postmortem brain tissue was obtained from 20 individuals with schizophrenia (SZ) and 20 neuropsychiatrically normal comparison subjects. Gray matter samples were extracted from two brain regions implicated in the disorder: Brodmann Area 10 and caudate. Affymetrix Human Gene 1.0 ST arrays were used on four subjects per group to attain an initial profile of differential expression of transcribed elements within and across brain regions in SZ. Numerous genes of interest with altered mRNA transcripts were identified by microarray through the differential expression of particular exons and 3' untranslated regions (UTRs) between diagnostic groups. Select microarray results--including dysregulation of ENAH exon 11a and CPNE3 3'UTR--were verified by qRTPCR and replicated in the remaining independent sample of 16 SZ patients and 16 normal comparison subjects. These results, if further replicated, clearly illustrate the importance of Identifying transcriptomic variants in expression studies, and implicate novel candidate genes in the disorder.

SUBMITTER: Cohen OS

PROVIDER: S-EPMC3502694 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic analysis of postmortem brain identifies dysregulated splicing events in novel candidate genes for schizophrenia.

Cohen Ori S OS Mccoy Sarah Y SY Middleton Frank A FA Bialosuknia Sean S Zhang-James Yanli Y Liu Lu L Tsuang Ming T MT Faraone Stephen V SV Glatt Stephen J SJ

Schizophrenia research 20121009 1-3

The diverse spatial and temporal expression of alternatively spliced transcript isoforms shapes neurodevelopment and plays a major role in neuronal adaptability. Although alternative splicing is extremely common in the brain, its role in mental illnesses such as schizophrenia has received little attention. To examine this relationship, postmortem brain tissue was obtained from 20 individuals with schizophrenia (SZ) and 20 neuropsychiatrically normal comparison subjects. Gray matter samples were ...[more]

PMID: 23062752

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Project description:ObjectiveAlternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons and is associated with lower parvalbumin levels in schizophrenia.MethodTissue samples enriched in calretinin and parvalbumin interneurons were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4, respectively, from matched pairs of schizophrenia and comparison subjects. Transcript levels for pan-ErbB4, four ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2), parvalbumin, and calretinin were quantified by quantitative polymerase chain reaction (qPCR) in each layer. Transcript levels for myocardial infarction associated transcript (MIAT), which regulates ErbB4 splicing, were quantified in gray matter by qPCR and in parvalbumin interneurons by microarray.ResultsCalretinin and parvalbumin mRNAs were preferentially expressed in layers 2 and 4, respectively. In schizophrenia subjects, lower parvalbumin levels, higher CYT-1 and JM-a levels, and lower CYT-2 and JM-b levels were detected selectively in layer 4. In layer 4, the JM-a/JM-b ratio was inversely correlated with parvalbumin levels in schizophrenia subjects. MIAT levels were preferentially higher in parvalbumin interneurons in schizophrenia subjects.ConclusionsThese findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.

Project description:BACKGROUND: In pigs, the perinatal period is the most critical time for survival. Piglet maturation, which occurs at the end of gestation, leads to a state of full development after birth. Therefore, maturity is an important determinant of early survival. Skeletal muscle plays a key role in adaptation to extra-uterine life, e.g. glycogen storage and thermoregulation. In this study, we performed microarray analysis to identify the genes and biological processes involved in piglet muscle maturity. Progeny from two breeds with extreme muscle maturity phenotypes were analyzed at two time points during gestation (gestational days 90 and 110). The Large White (LW) breed is a selected breed with an increased rate of mortality at birth, whereas the Meishan (MS) breed produces piglets with extremely low mortality at birth. The impact of the parental genome was analyzed with reciprocal crossed fetuses. RESULTS: Microarray analysis identified 12,326 differentially expressed probes for gestational age and genotype. Such a high number reflects an important transcriptomic change that occurs between 90 and 110 days of gestation. 2,000 probes, corresponding to 1,120 unique annotated genes, involved more particularly in the maturation process were further studied. Functional enrichment and graph inference studies underlined genes involved in muscular development around 90 days of gestation, and genes involved in metabolic functions, such as gluconeogenesis, around 110 days of gestation. Moreover, a difference in the expression of key genes, e.g. PCK2, LDHA or PGK1, was detected between MS and LW just before birth. Reciprocal crossing analysis resulted in the identification of 472 genes with an expression preferentially regulated by one parental genome. Most of these genes (366) were regulated by the paternal genome. Among these paternally regulated genes, some known imprinted genes, such as MAGEL2 or IGF2, were identified and could have a key role in the maturation process. CONCLUSION: These results reveal the biological mechanisms that regulate muscle maturity in piglets. Maturity is also under the conflicting regulation of the parental genomes. Crucial genes, which could explain the biological differences in maturity observed between LW and MS breeds, were identified. These genes could be excellent candidates for a key role in the maturity.

Project description:Biomedical research studies have generated large multi-omic datasets to study complex diseases like Alzheimer's disease (AD). An important aim of these studies is the identification of candidate genes that demonstrate congruent disease-related alterations across the different data types measured by the study. We developed a new method to detect such candidate genes in large multi-omic case-control studies that measure multiple data types in the same set of samples. The method is based on a gene-centric integrative coefficient quantifying to what degree consistent differences are observed in the different data types. For statistical inference, a Bayesian hierarchical model is used to study the distribution of the integrative coefficient. The model employs a conditional autoregressive prior to integrate a functional gene network and to share information between genes known to be functionally related. We applied the method to an AD dataset consisting of histone acetylation, DNA methylation, and RNA transcription data from human cortical tissue samples of 233 subjects, and we detected 816 genes with consistent differences between persons with AD and controls. The findings were validated in protein data and in RNA transcription data from two independent AD studies. Finally, we found three subnetworks of jointly dysregulated genes within the functional gene network which capture three distinct biological processes: myeloid cell differentiation, protein phosphorylation and synaptic signaling. Further investigation of the myeloid network indicated an upregulation of this network in early stages of AD prior to accumulation of hyperphosphorylated tau and suggested that increased CSF1 transcription in astrocytes may contribute to microglial activation in AD. Thus, we developed a method that integrates multiple data types and external knowledge of gene function to detect candidate genes, applied the method to an AD dataset, and identified several disease-related genes and processes demonstrating the usefulness of the integrative approach.

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Transcriptomic analysis of postmortem brain identifies dysregulated splicing events in novel candidate genes for schizophrenia.

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Transcriptomic analysis of postmortem brain identifies dysregulated splicing events in novel candidate genes for schizophrenia.

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