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Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial-to-mesenchymal transition and neuronal differentiation

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48367 | GEO | 2013/08/20

SECONDARY ACCESSION(S): PRJNA209851

REPOSITORIES: GEO

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Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial-to-mesenchymal transition and neuronal differentiation

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. To identify TCF4-mediated gene expression changes in SH-SY5Y cells, experiments were conducted with two control (mock and GAPDH KD) and two TCF4 knockdown (KD1 and KD2) groups. Two non-overlapping siRNAs against TCF4 were designed and transfected over a 72h period to induce global knockdown of TCF4 transcripts. In parallel, cells were mock transfected (mock; transfection reagent only) and transfected with an unrelated siRNA against GAPDH (GAPDH KD) in order to control for background gene expression changes due to transfection, presence of dsRNA and activation of the cellular silencing machinery. After transfection, RNA was extracted from all cells, converted to cDNA and labelled for microarray hybridization. Each of the four treatment groups (mock, GAPDH KD, KD1 and KD2) contained three biological replicates which were processed at the same time using the Toray microarray platform.

2013-08-20 | E-GEOD-48367 | biostudies-arrayexpress

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome IV

Project description:We evaluate cellular phenotypic abnormalities and alterations in molecular pathways due to mutations in the gene TCF4 in cells derived from Pitt-Hopkins patients, in comparison with respective controls (parents).

2022-03-02 | GSE189121 | GEO

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome III

2022-03-02 | GSE159860 | GEO

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome II

2022-03-02 | GSE159859 | GEO

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome

2022-03-02 | GSE159392 | GEO

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex.

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

TCF4 regulatory gene networks in developing dorsal telencephalon

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

scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse

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

TCF4 germline mutation and adult-onset SHH medulloblastoma

Project description:Medulloblastoma (MB) is the most prevalent pediatric cerebral cancer, but is rare in adults. The vast majority of MB arises sporadically but some few cases occur in association with germline alterations in genes such as PTCH1, SUFU, APC, and TP53. Additional genes are responsible for MB predisposition including some that have probably not been described so far either due to the rarity of the cases and/or to the low penetrance. Here we report the case of a 27 years old woman affected by Pitt Hopkins syndrome due to a heterozygous germline pathogenic variant in TCF4 who has developed a Sonic Hedgehog (SHH)-driven MB. Somatic loss of function variants of TCF4 have been identified in SHH MB especially among adults and this case raises the question of a predisposition to late-onset SHH MB associated with TCF4 germline alteration.

2019-02-14 | GSE126545 | GEO

Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion

Project description:The establishment of neural circuits depends on precise neuronal positioning in the cortex, a tightly coordinated process of neuronal differentiation, migration and terminal localization. Deficit in this process is implicated in several psychiatric disorders. Here, we show that the transcription factor Tcf4 controls neuronal positioning during brain development. Tcf4-deficient neurons become mispositioned in clusters when their migration to the cortical plate is complete. We reveal that Tcf4 regulates the expression of cell adhesion molecules to control neuronal positioning. Furthermore, through in vivo extracellular electrophysiology, we show that neuronal functions are disrupted after the loss of Tcf4. TCF4 mutations are strongly associated with schizophrenia and cause Pitt-Hopkins syndrome, which is characterized by severe intellectual disability. Thus, our results not only reveal the importance of neuronal positioning in brain development and but also provide new insights into the potential mechanisms underlying neurological defects linked to TCF4 mutations.

2021-09-20 | GSE166412 | GEO

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