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Genome-wide gene expression profiling post PCCB knockdown in human forebrain organoids

ABSTRACT: We established PCCB knockdown human induced pluripotent stem cell (hiPSC) line using CRISPR interference (CRISPRi). The established PCCB knockdown and control hiPSCs were then used to generate human forebrain organoids (hFOs). On day 60 of organoid culture, PCCB knockdown and control hFOs were randomly selected for RNA-sequencing (RNA-seq). We found that differentially expressed genes (DEGs) affected by PCCB knockdown were enriched with GABAergic synapse, synaptic vesicle cycle, neurotransmitter transport, forebrain development, axon development, synaptic organization, and calcium signaling pathways. The DEGs were also significantly overlapped with schizophrenia (SCZ)-associated genes, including genes dysregulated in brains or organoids derived from SCZ patients, and genes reported in SCZ GWAS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226233 | GEO | 2023/05/02

REPOSITORIES: GEO

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Genome-wide gene expression prolifing post-valproic acid exposure in human forebrain organoids

Project description:Human forebrain organoids (day 42) derived from U1M and U2F iPS cell lines were exposed with or without 1 mM valproic acid (VPA) for 72h. Organoids were then randomly selected for RNA sequencing, we found that differentially expressed genes (DEGs) induced by VPA exposure that shared in both U1M and U2F were enriched with neural development, synaptic transmission, calcium and potassium signaling pathways. The DEGs were also significantly enriched with autism spectrum disorder (ASD)-associated genes, including genes dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules.

2021-11-05 | GSE187006 | GEO

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

Project description:Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that 42 SCZ-related genes are regulated by POU3F2 in knockdown and RNA sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which impacts POU3F2 binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

2020-12-01 | GSE143692 | GEO

Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK801-Exposed C57BL/6 Mice.

Project description:MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia(SCZ). However, the effects of MK-801 treatment on gene expression in prefrontal cortex (PFC) are largely unknown. We have established MK-801 animal models to explore the etiology and pathophysiology of schizophrenia. Transcriptome analysis of the prefrontal cortex reveals that the differentially expressed genes mainly aggregate in chemical synaptic transmission and immune system process. Gene association patterns which are involved in synaptic vesicle cycle and mitochondrial electron transport chain have also been altered. Together, these observations underscore that dysfunction in glutamatergic synaptic vesicle cycle and mitochondrial electron transport chain has an impact on the pathogenesis of SCZ.

2019-03-12 | GSE111708 | GEO

Proteome landscape of schizophrenia in patient-derived cerebral organoids

Project description:We utilized patient-derived induced pluripotent stem cells (iPSCs) to generate 3D cerebral organoids to model neuropathology of Scz during this critical period. We discovered that Scz organoids exhibited ventricular neuropathology resulting in altered progenitor survival and disrupted neurogenesis. cz organoids principally differed not in their proteomic diversity, but specifically in their total quantity of disease and neurodevelopmental factors at the molecular level. Provides unique insights into the proteome landscape of schizophrenia in patient-derived cerebral organoids

2021-11-17 | PXD027812 | Pride

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2020-11-18 | GSE156396 | GEO

Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia

Project description:Genetic studies have suggested a role for glial pathology in the genesis of schizophrenia (SCZ). To assess the nature of SCZ-associated human glial dysfunction in vivo, we established human glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotential cells (hiPSCs), derived from patients with juvenile-onset schizophrenia or healthy controls. To this end, hiPSC GPCs were implanted neonatally into either immunodeficient myelin wild-type mice, in which donor GPCs remained as progenitors or became astrocytes, or into myelin-deficient shiverer mice, in which the GPCs also gave rise to oligodendrocytes. When implanted into shiverers, the SCZ-derived GPCs exhibited less expansion in the white matter than did control GPCs, instead migrating prematurely into the cortex. The SCZ GPC-transplanted shiverers were consequently hypomyelinated relative to control GPC-engrafted mice. When established instead in myelin wild-type hosts, the SCZ hiPSC glial chimeras manifested markedly delayed and diminished astrocytic differentiation, which was associated with diminished prepulse inhibition and an aberrant behavioral phenotype across multiple modalities. Accordingly, RNA-seq revealed significant differences in both glial differentiation-associated and synaptic gene expression by SCZ GPCs. These data suggest a potent contribution of cell-autonomous glial dysfunction to the development of schizophrenia, and provide a model for the in vivo assessment of human glial pathology in this disorder.

2017-07-20 | GSE86906 | GEO

Regulation of synaptic connectivity in schizophrenia by mutual neuron-microglia interaction

Project description:The examination of post-mortem brain tissue suggests synaptic loss as a central pathological hallmark of schizophrenia spectrum (SCZ), which is potentially related to activated microglia and increased inflammation. Induced pluripotent stem cells serve as a source for neurons and microglia-like cells to address neuron-microglia interactions. Here, we present a co-culture model of neurons and microglia, both of human origin, to show increased susceptibility of neurons to microglia-like cells derived from SCZ patients. Analysis of IBA-1 expression, NFκB signaling, transcription of inflammasome-related genes, and caspase-1 activation shows that enhanced, intrinsic inflammasome activation in patient-derived microglia exacerbates neuronal deficits such as synaptic loss in SCZ. Anti-inflammatory pretreatment of microglia with minocycline specifically rescued aberrant synapse loss in SCZ and reduced microglial activation. These findings open up possibilities for further research in larger cohorts, focused clinical work and longitudinal studies that could facilitate earlier therapeutic intervention.

2022-09-16 | GSE213232 | GEO

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex

Project description:Genome-wide association studies indicate allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. As a result, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA. However, there remains a gap in using LNPs to regulate gene and protein expression in the brain. To study the delivery of nucleic acids by LNPs to the brain, we found that LNPs released miR137 cargo and inhibited synaptic target transcripts in neuronal cultures. Biodistribution of LNPs loaded with firefly luciferase mRNA remained localized to the mouse prefrontal cortex (PFC) injection site without circulating to off-target organs. LNPs encapsulating Cre mRNA preferentially co-expressed in neuronal over microglial or astrocytic cells. Using quantitative proteomics, we found miR137 modulated glutamatergic synaptic protein networks that are commonly dysregulated in SCZ. These studies support engineering the next generation of brain-specific LNPs to deliver personalized RNA therapeutics and improve symptoms of central nervous system disorders.

2023-09-05 | PXD041648 | Pride

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [bulk RNA-seq]

Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients’ families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis.

2022-01-12 | GSE181024 | GEO

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [single-cell RNA-seq]

2022-01-12 | GSE181021 | GEO

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