Deconvolution of Transcriptional Networks Identifies TCF4 as a Master Regulator in Schizophrenia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE128333 | GEO | 2019/09/17
REPOSITORIES: GEO
Similar Datasets
Project description:Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified TCF4 as a top candidate MR that may be dysregulated in SCZ. We validated TCF4 as a MR through enrichment analysis of TCF4-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted TCF4 targets by knocking down TCF4 in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed TCF4 gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that TCF4 may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.
| S-EPMC6739105 | biostudies-literature
Project description:Deconvolution of Transcriptional Networks Identifies TCF4 as a Master Regulator in Schizophrenia
| PRJNA527139 | ENA
Project description:Haplo-insufficiency of TCF4 induced by mutations or microdeletion of TCF4 gene causes Pitt-Hopkins Diseases. Recent gene association studies revealed that mutations of TCF4 is significantly associated with schizophrenia. But the role of TCF4 in developing neocortex is not known. The goal of this study is to identify TCF4 itranscriptional regulatory pathways in developing neocortex by analyzing transcriptomes of dorsal telencephalons of TCF4knockout, TCF4Heterozygote and WT littermates and comparing differential expressed genes between these genotypes.
2019-02-06 | GSE79663 | GEO
Project description:Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia whereas rare variants have been found in patients with intellectual disability (ID), developmental disorders and autism spectrum disorder (ASD). Haploinsufficiency of TCF4 also causes Pitt Hopkins syndrome (PTHS); a condition characterized by developmental delay, ID and autonomic dysfunction. To understand the role of TCF4 in these disorders, we have used chromatin immunoprecipitation and next generation sequencing (ChIP-seq) to identify the genomic binding sites for TCF4. In this study we identify 10,604 binding sites assigned to 5,437 genes. De novo motif enrichment found that approximately 77% of the TCF4 binding sites contained at least one E-box (5’-CAtcTG). Furthermore, the majority of TCF4 binding sites overlapped with H3K27ac histone mark for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P < 5.3 x 10-7), ASD (P < 2.5 x 10-4) and ID (P < 7.6 x 10-3) were also enriched among TCF4 targets. These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include genetic risk factors for common neurodevelopmental disorders.
2017-12-08 | GSE96915 | GEO
Project description:BACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS: In order to explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. Effects on cell proliferation were assessed using high content imaging. RESULTS: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. CONCLUSIONS: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in Pitt-Hopkins Syndrome and risk for schizophrenia.
2016-10-01 | GSE62085 | GEO
Project description:Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%1. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue2 and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD3, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder. 4 samples/no replicates/genotyped for copy number variation, using the same refrence sample on nimblegen's 080131_HG18_WG_CGH_v2DCR_HX1 design, a dual color microarry, 2.1 million probes platform.
2011-08-12 | E-GEOD-30737 | biostudies-arrayexpress
Project description:Early life stress (ELS) has often been described as a risk factor for developing psychiatric disease. However, moderate exposure to ELS can also lead to stress inoculation and consequently adaptive changes on brain and behavior. Moreover, the FKBP5 gene, encoding the FKBP51 co-chaperone, has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. However, the underlying mechanisms behind the interaction of FKBP51 and moderate ELS exposure are still not completely understood and particularly data in the female sex are scarce. In this study, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of moderate ELS was investigated in both sexes, by using the Fkbp5Nex conditional knockout line. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in in Fkbp5Nexx wild-type mice. Interactive effects of FKBP51 in glutamatergic forebrain neurons and moderate ELS exposure in female mice were also reflected on brain volume of different cortical regions, the subiculum and white matter structures. Furthermore, interactive effects were observed for structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of these interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the moderate ELS exposure. Taken together, this study shows that FKBP51 in glutamatergic forebrain neurons mediates adaptive effects of moderate ELS exposure on emotional regulation, cognitive behavior and neuronal structure and function. Moreover, it proposes TCF4 as an underlying target that drives the FKBP51-mediated effects of moderate ELS on brain and behavior.
2024-02-26 | GSE256468 | GEO
Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. Examination of TCF4 Isoform expression comparison between mutant and control skin fibroblast tissues
2016-05-31 | E-GEOD-77742 | biostudies-arrayexpress
Project description:In order to study the molecular mechanisms involving TCF4 in keratinocytes under different inflammatory responses, control and TCF4 knock down keratinocytes were stimulated with inflammatory cytokines and conducted RNA-seq to profile the gene expression.
2024-06-05 | GSE260642 | GEO
Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain.
2016-05-31 | GSE77742 | GEO