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Abrogation of WNT signaling by dominant-negative TCF4

ABSTRACT: To assess cellular changes upon abrogation of the WNT-signaling pathway, we induced expression of a dominant-negative T-cell factor 4 (TCF4). This showed a remarkable overlap with activation of the unfolded protein response (UTR) in the same colon cancer cell line. 500,000 cells were plated in a 10 cm2 plate, and the following day, treated for 20 hrs with doxycycline (Dox) or vehicle. Three independent biological replicates per treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Jarom Heijmans

PROVIDER: E-GEOD-28467 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Abrogation of WNT signaling by dominant-negative TCF4

Project description:To assess cellular changes upon abrogation of the WNT-signaling pathway, we induced expression of a dominant-negative T-cell factor 4 (TCF4). This showed a remarkable overlap with activation of the unfolded protein response (UTR) in the same colon cancer cell line.

2015-04-01 | GSE28467 | GEO

Complex Balanced Translocation Disrupting TCF4 and Altering TCF4 Isoform Expression Segregates as Mild Autosomal Dominant Intellectual Disability

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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Complex Balanced Translocation Disrupting TCF4 and Altering TCF4 Isoform Expression Segregates as Mild Autosomal Dominant Intellectual Disability

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Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

Project description:Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the encoded transcription factor TCF4 in Î²-cells. Here, a mouse genetics approach shows that removal of TCF4 from Î²-cells does not affect their function, while manipulating TCF4 levels in the liver has major effects on metabolism. In Tcf7l2-/- mice, the immediate postnatal surge in liver metabolism does not occur. Consequently, pups die due to hypoglycemia. Combining chromatin immunoprecipitation with gene expression profiling, we identify a TCF4-controlled metabolic gene program that is acutely activated in the postnatal liver. In concordance, adult liver-specific Tcf7l2 knockout mice show reduced hepatic glucose production during fasting and display improved glucose homeostasis when maintained on high-fat diet. Furthermore, liver-specific TCF4 overexpression increases hepatic glucose production. These observations imply that TCF4 directly activates metabolic genes, and that inhibition of Wnt signaling may be beneficial in metabolic disease. RNA was extracted from liver tissues of the Tcf7l2 wildtype or knockout mice with treatments as indicated. Microarray analysis was performed to compare the expression profile changes between Tcf7l2 knockout and wildtype mice in response to treatment.

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Induction of ER stress in the colon cancer cell line LS174 with SubAB

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Cytokine stimulated keratinocytes (TCF4 KD)

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.

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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.

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