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Protein arginine methyltransferase 7 is linked to schizophrenia by regulating the function of neural progenitor cell

ABSTRACT: Schizophrenia (SCZ) is a severe mental disorder with strong heritability and complex inheritance, which affects about 1% of populations worldwide. In this study, we prioritized protein arginine methyltransferase 7 (PRMT7) for SCZ susceptibility. Next, we explored the cellular and molecular infrastructures conferring PRMT7 to SCZ risk. Down-regulation of PRMT7 in neural progenitor cells (NPCs) caused decreased proliferation and increased neuronal differentiation. Additionally, the differentiated neurons derived from these NPCs displayed longer neurites compared to controls. Conversely, Over-expression of PRMT7 led to enhanced NPC proliferation and reduced neuronal differentiation. Moreover, in 3D cerebral organoids, the similar NPC phenotypic changes were observed following PRMT7 depletion. Mechanistically, the expression of genes related to cell cycle and neuronal functions were under regulation of PRMT7 via depositing H4R3me2s on their promoter regions. Disease enrichment analysis revealed that these PRMT7-regulated genes were more strongly associated with SCZ compared to other mental disorders. In summary, this study uncovers that PRMT7 is a functional gene at 16q22.1 contributing to the etiology of SCZ by impacting the proliferation and differentiation of NPCs as an epigenetic regulator.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284672 | GEO | 2024/12/19

REPOSITORIES: GEO

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Protein arginine methyltransferase 7 is linked to schizophrenia by regulating the function of neural progenitor cell

Project description:Schizophrenia (SCZ) is a severe mental disorder with strong heritability and complex inheritance, which affects about 1% of populations worldwide. In this study, we prioritized protein arginine methyltransferase 7 (PRMT7) for SCZ susceptibility. Next, we explored the cellular and molecular infrastructures conferring PRMT7 to SCZ risk. Down-regulation of PRMT7 in neural progenitor cells (NPCs) caused decreased proliferation and increased neuronal differentiation. Additionally, the differentiated neurons derived from these NPCs displayed longer neurites compared to controls. Conversely, Over-expression of PRMT7 led to enhanced NPC proliferation and reduced neuronal differentiation. Moreover, in 3D cerebral organoids, the similar NPC phenotypic changes were observed following PRMT7 depletion. Mechanistically, the expression of genes related to cell cycle and neuronal functions were under regulation of PRMT7 via depositing H4R3me2s on their promoter regions. Disease enrichment analysis revealed that these PRMT7-regulated genes were more strongly associated with SCZ compared to other mental disorders. In summary, this study uncovers that PRMT7 is a functional gene at 16q22.1 contributing to the etiology of SCZ by impacting the proliferation and differentiation of NPCs as an epigenetic regulator.

2024-10-01 | GSE266062 | 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

Delayed cell cycling in DS Ts1Cje neural precursor cells results in gene expression dysregulation

Project description:Down syndrome neurophenotypes are characterized by mental retardation and a decreased brain volume. In order to identify whether deficits in proliferation, differentiation or survival could be responsible for this phenotype, neural precursor cells (NPCs) were isolated from the developing E14 neocortex of Down syndrome partial trisomy Ts1Cje mice and euploid (WT) littermates. Proliferation, cell differentiation and cell death assays revealed that Ts1Cje NPCs proliferated at a slower rate, due to a longer cell cycle and that a greater number of cells were positive for glial fibrillary acidic protein. An increase in Ts1Cje NPC cell death was also noted. Gene expression profiling was conducted on RNA extracted from Ts1Cje and WT NPCs. Approximately 54% of triploid gene expression ratios were significantly greater than the expected diploid gene ratio of 1.0. A number of diploid genes associated with differentiation, glial function and proliferation were dysregulated. The evidence points to a delay in cellular cycling that could exert stress on the NPC population, which might result in cellular death and a mobilization of glial cell survival responses. Importantly, these phenotypic changes, which mimic those seen in Down syndrome individuals, do not require over-expression of amyloid precursor protein (App) or soluble superoxide dismutase 1 (Sod1). In conclusion, early developmental proliferation deficits in Down syndrome result in secondary morphological changes that can impact on cognitive development and function. Keywords: Down syndrome, Neocortical precursor cells, transcriptome, proliferation Neural precursor cells (NPCs) were isolated from mouse E14 neocortex of Down syndrome Ts1Cje mice and euploid littermates. We compared gene expression profiles from trisomic and wild-type cells using pangenomic microarrays.

2010-05-19 | E-GEOD-9805 | biostudies-arrayexpress

Transcriptomic signatures of risk genes implicated in psychiatric disorders during neuronal differentiation

Project description:Susceptibility genes for Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), monogenetic disorders with intellectual disabilities (ID) or schizophrenia (SCZ) converge on processes related to neuronal function and differentiation. Furthermore, ASD risk genes are enriched for FMRP (Fragile X Mental Retardation Protein) targets and for genes implicated in ID. In addition, a significant co-heritability was observed between ASD and SCZ. The genetic overlap between ASD, FXS, ID and SCZ together with the symptomatic differences gives rise to the question if pathomechanisms impair the same or different regulatory patterns activated during neuronal differentiation (ND). To test this idea, we performed transcriptome analysis of in-vitro differentiation of the neuroblastoma cell line model SH-SY5Y and identified genes that were differentially expressed, dynamically regulated, and coordinately expressed. The identified genetic modules activated during ND are enriched for genetic risk factors for these four disorders. Although risk genes for the disorders significantly overlap, we observed disorder specific enrichments: ASD or FXS implicated genes were likely to be positive regulators of ND whereas ID implicated genes were related to negative regulation. ASD and SCZ genes were specifically enriched among cholesterol and fatty acid associated modules. ID genes were overrepresented among cell cycle modules. In addition, we show that ASD genes are likely to be hub genes. We hypothesize that knowledge about genetic variants of an individual combined with network and pathway context of the related genes will allow differentiating between psychiatric disorders. 21 samples, consisting of 3 replicates harvested at 7 different time-points of RA+BDNF-induced neuronal differentiation

2016-06-01 | E-GEOD-69838 | biostudies-arrayexpress

ZIKV-infected human NPCs LC-MS

Project description:In this study, proteomic analysis on ZIKV-infected primary human fetal neural progenitor cells (NPCs) revealed that virus infection altered levels of cellular proteins involved in NPC proliferation, differentiation and migration.

2018-06-25 | PXD009343 | Pride

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

Integrity of the short arm of nuclear pore Y-complex is required for mouse embryonic stem cell growth and differentiation

Project description:Nuclear pore complexes (NPCs) are established players in cell division and differentiation. However studies on the contribution of individual NPC subunits to these processes are still scarce. Here we have used mouse embryonic stem cells (mESCs) to characterize the role of structural components of the NPCs, focusing on the short arm of the Y-complex that comprises Nup85, Seh1 and Nup43. We show that Seh1 and Nup43, although dispensable at the pluripotent stage, are required for normal cell growth rates at that stage and for mESC viability upon differentiation. Lack of Seh1 or Nup43 in mESCs is associated with a mild reduction of NPC density that is also observed when Seh1 interaction with Nup85 is impaired. Nevertheless, mESC proliferation and differentiation are not altered in these ∆E2-GFP-Nup85 mutants, indicating that it is the integrity of the Y-complex, rather than the number of NPCs, that is critical to ensure these processes.

2021-05-20 | PXD022190 | Pride

Delayed cell cycling in DS Ts1Cje neural precursor cells results in gene expression dysregulation

2009-04-30 | GSE9805 | GEO

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

2015-09-14 | GSE71289 | GEO

Activating transcription factors Atf3/Atf4 drive early molecular events preceding neural stem cell differentiation and control neuron formation [Long]

Project description:The generation of new neurons from neural stem cells is tightly controlled by transcriptional programs. To induce cell fate switches that establish neuronal identities, differentiating neural precursor cells (NPCs) must undergo rapid and dynamic gene expression changes. However, the neuronal fate-determining molecular events that precede NPC differentiation are incompletely understood. Using high temporal resolution transcriptional profiling of adult hippocampal NPC differentiation, we here identified the activating transcription factors Atf3 and Atf4 as early switch regulators that drive NPC fate and control neuron formation. We found that Atf3/4 are rapidly upregulated in NPCs upon induction of differentiation and drive dynamic gene expression changes associated with neurogenesis. Pharmacological and genetic perturbation of Atf4 demonstrated its importance for neuron formation. Sustained overexpression of Atf3 hampered neurogenesis by repressing long non-coding RNA Miat. Our results demonstrate the critical role of an Atf3/Atf4-controlled transcriptional network in driving early molecular events during neurogenesis.

2024-01-18 | GSE253304 | GEO

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