Human iPSC-derived neuronal cells from CTBP1-mutated patients reveal altered expression of neurodevelopmental gene networks
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ABSTRACT:
PROVIDER: PRJNA666426 | ENA |
REPOSITORIES: ENA
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Project description:A recurrent de novo mutation in the transcriptional corepressor CTBP1 is associated with neurodevelopmental disabilities in children (Beck et al., 2016; Beck et al., 2019; Sommerville et al., 2017). All reported patients harbor a single recurrent de novo heterozygous missense mutation (p.R342W) within the cofactor recruitment domain of CtBP1. To investigate the transcriptional activity of the pathogenic CTBP1 mutant allele in physiologically relevant human cell models, we generated induced pluripotent stem cells (iPSC) from the dermal fibroblasts derived from patients and normal donors. The transcriptional profiles of the iPSC-derived ‘early’ neurons were determined by RNA-sequencing. Comparison of the RNA-seq data of the neurons from patients and normal donors revealed down regulation of gene networks involved in neurodevelopment, synaptic adhesion and anti-viral (interferon) response. Consistent with the altered gene expression patterns, the patient-derived neurons exhibited morphological and electrophysiological abnormalities, and susceptibility to viral infection. Taken together, our studies using iPSC-derived neuron models provide novel insights into the pathological activities of the CTBP1 p.R342W allele.
2020-09-30 | GSE158754 | GEO
Project description: Not available
| S-EPMC7653094 | biostudies-literature
Project description:We previously reported a pathogenic de novo W342 mutation in the transcriptional corepressor CtBP1 in four independent patients with neurodevelopmental disabilities. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CtBP1 mutation. Within this cohort we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia and tooth enamel defects present in all patients. The W342 mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cells lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.
2019-05-09 | PXD012702 | Pride
Project description:We previously reported a pathogenic de novo W342 mutation in the transcriptional corepressor CtBP1 in four independent patients with neurodevelopmental disabilities. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CtBP1 mutation. Within this cohort we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia and tooth enamel defects present in all patients. The W342 mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cells lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.
2019-02-08 | GSE126253 | GEO
Project description:Dilated cardiomyopathy (DCM), a myocardial disorder that can result in progressive heart failure and arrhythmias, is defined by ventricular chamber enlargement and dilatation, and systolic dysfunction. To decipher the basis for the cardiac pathology in titin-mutated patients, we investigated the hypothesis that induced Pluripotent Stem Cell (iPSC)- derived cardiomyocytes (iPSC-CM) generated from patients, recapitulate the disease phenotype.Our findings show that the mutated cardiomyocytes from DCM patients recapitulate abnormalities of the inherited cardiomyopathies.
2019-04-12 | PXD010513 | Pride
Project description:Prostate cancer is the most common cancer in men and Androgen receptor (AR) downstream signalings promote prostate cancer cell proliferation. We identified androgen-regulated long non-coding RNA, CTBP1-AS, located in the antisese region of CTBP1 gene. CTBP1-AS activate AR signaling by epigenetically repress AR-associated cofactors such as CTBP1 by interactign with RNA-binding protein PSF and recruiting HDAC complex to the target promoters. In order to investigate the CTBP1-AS and PSF function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siPSF or siCTBP1-AS treatment. We also treated cells with vehicle or androgen to analyzed the effects of CTBP1-AS and PSF on AR function. Observation of androgen dependent gene expression changes after treatmet with siRNAs targeting CTBP1-AS and PSF with microarray.
2014-01-01 | E-GEOD-44264 | biostudies-arrayexpress
Project description:To discover the regulatory role of CTBP1/2 in high grade serous ovarian cancer, The full cDNA was extracted from SKOV3 shRNA control and CtBP1/2 knockdown and then compared the expression profiles of them to discovery the key functions and pathways regulated by CtBP1/2..
2022-05-21 | GSE175425 | GEO
Project description:Cells were transfected with siRNA targetting CtBP1, or a non-targetting control siRNA. mRNA was extracted for gene expression analysis 48 hours after transfection
2017-02-03 | E-MTAB-3295 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and Androgen receptor (AR) downstream signalings promote prostate cancer cell proliferation. We identified androgen-regulated long non-coding RNA, CTBP1-AS, located in the antisese region of CTBP1 gene. CTBP1-AS activate AR signaling by epigenetically repress AR-associated cofactors such as CTBP1 by interactign with RNA-binding protein PSF and recruiting HDAC complex to the target promoters. In order to investigate the CTBP1-AS and PSF function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siPSF or siCTBP1-AS treatment. We also treated cells with vehicle or androgen to analyzed the effects of CTBP1-AS and PSF on AR function.
2014-01-01 | GSE44264 | GEO
Project description:The pluripotency-associated transcriptional network is regulated by a core circuitry of transcription factors. The PR domain-containing protein, PRDM14, maintains pluripotency by activating and repressing transcription in a target gene-dependent manner. However, the mechanisms underlying dichotomic switching of PRDM14-mediated transcriptional control remains elusive. Here, we identified C-terminal binding protein 1/2 (CtBP1/2) as components of the PRDM14-mediated repressive complex. CtBP1/2 binding to PRDM14 depends on CBFA2T2, a core component of the PRDM14 complex. The loss of Ctbp1/2 impaired the PRDM14-mediated transcriptional repression required for pluripotency maintenance and primed to naïve pluripotency transition. Furthermore, CtBP1/2 also interacted with the PRC2 complexes, and the loss of Ctbp1/2 impaired the PRC2 and H3K27me3 enrichment at the target genes upon PRDM14 overexpression. These results suggest that evidence that the target gene-dependent transcriptional activity of PRDM14 is regulated by partner switching to ensure transition from primed to naïve pluripotency.
2020-07-15 | GSE134666 | GEO