A novel human organoid model system reveals requirement of TCF4 for 2 oligodendroglial differentiation
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ABSTRACT:
PROVIDER: PRJEB87238 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR14750344_1.fastq.gz | Fastqsanger.gz | |||
| ERR14750344_2.fastq.gz | Fastqsanger.gz | |||
| ERR14750345_1.fastq.gz | Fastqsanger.gz | |||
| ERR14750345_2.fastq.gz | Fastqsanger.gz | |||
| ERR14750346_1.fastq.gz | Fastqsanger.gz |
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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
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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.
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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.
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Project description:TCF4 is an important neurodevelopmental transcription factor associated with schizophrenia and Pitt-Hopkins syndrome. In this study, we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-β signaling, epithelial-to-mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators SNAI2 and DEC1 and the proneural genes NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (AS), ZEB2 (MWS) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes.
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