ScRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse
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ABSTRACT:
PROVIDER: PRJNA613496 | ENA |
REPOSITORIES: ENA
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Project description:The bHLH transcription factor TCF4 plays an important role in neurodevelopment highlighted by its association with schizophrenia and Pitt-Hopkins-Syndrome. Here we demonstrate that TCF4 function is essential for forebrain commissure formation in mice. Single-cell RNA sequencing of TCF4 knockout neocortices revealed dysregulation of multiple gene regulatory networks. We provide evidence that TCF4 controls the underlying regulons by interaction with the regulators, transcription factors surprisingly not belonging to the known canonical interactors of the bHLH family. In-depth analysis of the interplay between TCF4 and SOX11 showed a synergistic effect on commissural formation. Mice haploinsufficient for Sox11 or Tcf4 showed no commissural phenotype or only a mild callosal shortening, respectively, whereas Tcf4/Sox11 double haploinsufficient mice display aggravated corpus callosum dysgenesis and anterior commissure agenesis. Moreover, TCF4 and SOX11 synergistically induce the expression of common target genes. Collectively, these findings illuminate how TCF4 dysregulation influences brain development and contributes to neurodevelopmental diseases.
2021-07-04 | GSE147247 | GEO
Project description: Not available
| S-EPMC8327186 | biostudies-literature
Project description:We combined loss-of-function RNA interference screening and a high-throughput drug toxicity screening to define novel therapeutic targets in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy for which no curative therapy exists. The E-box transcription factor TCF4 emerged as the master transcriptional regulator of the BPDCN oncogenic program, a finding that can be exploited for the accurate molecular diagnosis of BPDCN. Genetic interference with the TCF4-dependent network induced a rewiring of BPDCN gene expression, resulting in apoptosis. Treatment of BPDCN lines with bromodomain and extra-terminal domain inhibitors (BETi's) down regulated TCF4 and its target gene network, inducing apoptosis both in vitro and retarding growth of BPDCN xenografts in vivo, supporting the clinical evaluation of BETi's in this lethal cancer.
2016-11-15 | GSE75650 | GEO
Project description:We combined loss-of-function RNA interference screening and a high-throughput drug toxicity screening to define novel therapeutic targets in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy for which no curative therapy exists. The E-box transcription factor TCF4 emerged as the master transcriptional regulator of the BPDCN oncogenic program, a finding that can be exploited for the accurate molecular diagnosis of BPDCN. Genetic interference with the TCF4-dependent network induced a rewiring of BPDCN gene expression, resulting in apoptosis. Treatment of BPDCN lines with bromodomain and extra-terminal domain inhibitors (BETi's) down regulated TCF4 and its target gene network, inducing apoptosis both in vitro and retarding growth of BPDCN xenografts in vivo, supporting the clinical evaluation of BETi's in this lethal cancer.
2016-11-15 | GSE76147 | GEO
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi's) induce BPDCN apoptosis, which was attributable to disruption of the TCF4-dependent transcriptional network and loss of BPDCN-specific super-enhancers. BETi's retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.
2016-11-15 | GSE84623 | GEO
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi's) induce BPDCN apoptosis, which was attributable to disruption of the TCF4-dependent transcriptional network and loss of BPDCN-specific super-enhancers. BETi's retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.
2016-11-15 | GSE84471 | GEO
Project description:To depict the gene regulatory network of TCF4 in interneuron development, We performed chromatin immunoprecipitation-sequencing (ChIP seq) on human medial ganglionic eminence-like organoids (hMGEOs) to identify genome-wide TCF4 binding sites. This study provides compelling evidence to support the biological rationale linking TCF4 to the developing cortical interneuron.
2023-06-19 | GSE235071 | GEO
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: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: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