Dataset Information

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons.

ABSTRACT: Importance:Schizophrenia candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons. One important next step is to further our understanding on the role of activity-dependent changes of gene expression in the etiopathogenesis of schizophrenia. Objective:To examine whether neuronal activity-dependent changes of gene expression are dysregulated in schizophrenia. Design, Setting, and Participants:Neurons differentiated from human-induced pluripotent stem cells derived from 4 individuals with schizophrenia and 4 unaffected control individuals were depolarized using potassium chloride. RNA was extracted followed by genome-wide profiling of the transcriptome. Neurons were planted on June 21, 2013, and harvested on August 2, 2013. Main Outcomes and Measures:We performed differential expression analysis and gene coexpression analysis to identify activity-dependent or disease-specific changes of the transcriptome. Gene expression differences were assessed with linear models. Furthermore, we used gene set analyses to identify coexpressed modules that are enriched for schizophrenia risk genes. Results:We identified 1669 genes that were significantly different in schizophrenia-associated vs control human-induced pluripotent stem cell-derived neurons and 1199 genes that are altered in these cells in response to depolarization (linear models at false discovery rate ?0.05). The effect of activity-dependent changes of gene expression in schizophrenia-associated neurons (59 significant genes at false discovery rate ?0.05) was attenuated compared with control samples (594 significant genes at false discovery rate ?0.05). Using gene coexpression analysis, we identified 2 modules (turquoise and brown) that were associated with diagnosis status and 2 modules (yellow and green) that were associated with depolarization at a false discovery rate of ?0.05. For 3 of the 4 modules, we found enrichment with schizophrenia-associated variants: brown (?2?=?20.68; P?=?.002), turquoise (?2?=?12.95; P?=?.04), and yellow (?2?=?15.34; P?=?.02). Conclusions and Relevance:In this analysis, candidate genes clustered within gene networks that were associated with a blunted effect of activity-dependent changes of gene expression in schizophrenia-associated neurons. Overall, these findings link schizophrenia candidate genes with specific molecular functions in neurons, which could be used to examine underlying mechanisms and therapeutic interventions related to schizophrenia.

SUBMITTER: Roussos P

PROVIDER: S-EPMC5437975 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons.

Roussos Panos P Guennewig Boris B Kaczorowski Dominik C DC Barry Guy G Brennand Kristen J KJ

JAMA psychiatry 20161101 11

<h4>Importance</h4>Schizophrenia candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons. One important next step is to further our understanding on the role of activity-dependent changes of gene expression in the etiopathogenesis of schizophrenia.<h4>Objective</h4>To examine whether neuronal activity-dependent changes of gene expression are dysregulated in schizophrenia.<h4>Design, setting, and participants</h4>Neurons differentiated ...[more]

PMID: 27732689

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Project description:BackgroundDuplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.MethodsWe have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.ResultsAnalysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.ConclusionsChromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.

Project description:BackgroundSchizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold.MethodsTo dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures.ResultsIn iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation.ConclusionsOur results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.

Dataset Information

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons.

Publications

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons.

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