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Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders

ABSTRACT: Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57821 | GEO | 2014/08/01

SECONDARY ACCESSION(S): PRJNA248182

REPOSITORIES: GEO

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Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders

Project description:Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders. Two patient derived iPSC lines carrying heterozygous 4bp deletion in DISC1 gene and 1 related control were analyzed in biological triplicate

2014-08-01 | E-GEOD-57821 | biostudies-arrayexpress

Human Neuron Proteome Altered by Disrupted in schizophrenia 1 (DISC1) Mutations

Project description:Disrupted in schizophrenia 1 is a protein that is encoded by the DISC1 gene in humans. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, synapse formation and maturation, synaptic transmission, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, major depression, bipolar disorder, and other psychiatric conditions. The cellular functions that are disrupted by permutations in DISC1, which lead to the development of these disorders, have yet to be clearly defined and are the subject of current ongoing research.

2021-09-08 | PXD013391 | Pride

RNA-seq of oligodendroglia progenitor cells(OPCs) isolated from WT and DISC1-Δ3 mice

Project description:Disrupted-in-schizophrenia-1 (DISC1), as one of the schizophrenia susceptibility genes highly expressed in oligodendrocyte precursor cells (OPCs), impacts oligodendroglial differentiation and myelination. Several DISC1 splicing variants, including DISC1-Δ3 (a DISC1 transcript with deleted exon 3 in a single allele), are abnormally upregulated in human schizophrenia patients, however, how they trigger the onset of the disease has not been explored yet. Here, we generate a mouse line that mimics human DISC1-Δ3 in oligodendrocyte lineage cells, and demonstrate that hypertrophic OPCs rather than myelin, are responsible for the neuronal deficits and schizophrenia-like symptoms. RNAseq was performed to analyze the transcriptome change in DISC1-Δ3 OPC, revealing that DISC1-Δ3 elevates the Wnt pathway activity in OPCs, which promotes Wif1 expression, thereby leading to disrupted synapse formation in neighboring neurons. Interfering or knockout of Wif1 in DISC1-Δ3 OPCs could rescue neuronal synaptic and functional deficits in our mouse model. Our findings shed light on the myelination-independent role of OPCs on the onset of schizophrenia, and may pave the way for new rational lines of inquiry in developing therapeutic strategies for schizophrenia.

2022-12-28 | GSE183341 | GEO

Transcriptome profiling of human neural progenitor cells and neurons with DISC1 interruption

Project description:Purpose: Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We sought to compare the gene expression profiles of human neural progenitor cells (NPCs) and neurons with interruption of the DISC1 gene in exon 2 (affecting all known coding transcripts) or exon 8 (near the site of the Scottish translocation, affecting longer transcripts). Methods: Wild-type and DISC1-targeted iPSCs (wild-type = "WT", exon 8 single allelic frameshift mutant = "ex8_wm", exon 8 biallelic frameshift mutant = "ex8_mm", exon 2 biallelic frameshift mutant = "ex2mm") were differentiated to NPCs and neurons using an embryoid aggregate method. NPC or neuronal cultures were used for RNA harvest and subsequent paired-end stranded sequencing of >50M reads/sample and 3-6 biological replicates per group. Results: We find that a subset of genes related to neuronal differentiation and development are dysregulated with DISC1 disruption at the NPC timepoint, whereas expression of genes related to neuronal function and signaling are altered at the neuronal timepoint. This study implicates DISC1 as a regulator of neuronal development. mRNA profiles of wild-type and DISC1-targeted human iPSC-derived neural progenitor cells (day 17) and neurons (day 50) by paired-end sequencing, with 3-6 biological replicates, using Illumina HiSeq

2015-09-14 | E-GEOD-71289 | biostudies-arrayexpress

Proteomics of rat overexpressing human DISC1 in the dorsal striatum

Project description:Disrupted-in-schizophrenia 1 (DISC1) is a key protein involved in behavioral processes and various mental disorders, including schizophrenia and major depression. A transgenic rat modestly overexpressing non-mutant human DISC1, modeling aberrant proteostasis of the DISC1 protein, displays behavioral, biochemical and anatomical deficits consistent with aspects of mental disorders, including changes in the dorsal striatum, an anatomical region critical in the development of behavioral disorders. Here, the dorsal striatum of 10 tgDISC1 and 10 littermate control rats was used for synaptosomal membrane preparations and for performing LC-MS-based quantitative proteomics, using TMT 10plex. Enrichment analysis was generated from proteins with level changes. Canonical pathway analysis assigned proteins with level changes to actin cytoskeleton, Gαq, Rho family GTPase and Rho GDI-, axonal guidance, ephrin receptor and dopamine-DARPP32 feedback in cAMP signalling. Functional network components included proteins of the categories "quantity of neurons, extension of axons and neurites and long term potentiation". Our analysis demonstrates that the effects of a relatively small overexpression of non-mutant DISC1 or its missassembly has profound consequences on protein networks essential for behavioral control

2018-02-27 | PXD008123 | Pride

Transcriptome profiling of human neural progenitor cells and neurons with DISC1 interruption

2015-09-14 | GSE71289 | GEO

Endogenous Cell Type-Specific DISC1 Interactomes Reveal Protein Networks Associated to Neurodevelopmental Disorders

Project description:Disrupted in schizophrenia 1 (DISC1) has been implicated in contributing to a number of psychiatric diseases and neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed towards understanding the function of DISC1 through the determination of its protein-protein interactions within an in-vitro setting, endogenous interactions involving DISC1 within a cell-type specific setting relevant to neural development remain unclear.

2018-07-04 | PXD007103 | Pride

Topoisomerase 3b is essential for neuronal activity-dependent transcription, neurogenesis, and synaptic and behavioral neuroplasticity

Project description:Topoisomerase 3b (Top3b) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3b mutation has been linked to schizophrenia, autism, epilepsy, and cognitive impairment. However, whether and how Top3b mutations are causal to these disorders remain unclear. Here we show that Top3b knockout mice exhibit behavioral phenotypes related to psychiatric disorders and cognitive impairment, including increased anxiety and fear, abnormal social interactions, impaired context discrimination, and defective spatial learning and memory. In addition, these mice display deficits in adult hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many that are critical for neuronal functions and mental health. Our data suggest that Top3b is essential for normal brain function in multiple domains, and defective neuronal activity-dependent transcription may be a mechanism by which Top3b deletion causes cognitive impairment and psychiatric disorders.

2020-05-22 | GSE145730 | GEO

Temporal dysregulation of cortical gene expression in the isolation-reared Wistar rat

Project description:The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. Gene expression was assessed in social control and isolation reared rats at 4 increasing postnatal ages to relate gene expression dysregulation to behavioural and endophenotype emergence. We prepared cDNA from brain tissue samples of the medial prefrontal cortex from socially reared Wistar rats (Soc) and matching isolation reared cohorts (Iso) at postnatal day (P) 30, 40, 60 and 80.

2010-06-16 | E-GEOD-19653 | biostudies-arrayexpress

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress

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