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Derek J. Blake - One of the best experts on this subject based on the ideXlab platform.
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Effect of trinucleotide repeat expansion on the expression of TCF4 mRNA in fuchs’ endothelial corneal dystrophy
Investigative Opthalmology & Visual Science, 2019Co-Authors: Naoki Okumura, Masakazu Nakano, Kei Tashiro, Kengo Yoshii, Ross A. Aleff, Malinda L. Butz, Ryosuke Hayashi, Takahiko Sato, Derek J. Blake, W. Edward HighsmithAbstract:Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.
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the psychiatric risk gene transcription factor 4 TCF4 regulates neurodevelopmental pathways associated with schizophrenia autism and intellectual disability
Schizophrenia Bulletin, 2018Co-Authors: Marc P Forrest, Matthew Hill, Adrian James Waite, David H Kavanagh, Katherine E Tansey, Derek J. BlakeAbstract:Background Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia. Conversely, rare damaging TCF4 mutations cause Pitt–Hopkins syndrome and have also been found in individuals with intellectual disability (ID) and autism spectrum disorder (ASD). Methods Chromatin immunoprecipitation and next generation sequencing were used to identify the genomic targets of TCF4. These data were integrated with expression, epigenetic and disease gene sets using a range of computational tools. Results We identify 10604 TCF4 binding sites in the genome that were assigned to 5437 genes. De novo motif enrichment found that most TCF4 binding sites contained at least one E-box (5′-CAtcTG). Approximately 77% of TCF4 binding sites overlapped with the H3K27ac histone modification for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction, and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P = 5.3 × 10−7), ASD (P = 2.5 × 10−4), and ID (P = 7.6 × 10−3) were also enriched among TCF4 targets. TCF4 binding sites were also found at other schizophrenia risk loci including the nicotinic acetylcholine receptor cluster, CHRNA5/CHRNA3/CHRNB4 and SETD1A. Conclusions These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include many genetic risk factors for common neurodevelopmental disorders.
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Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability
Current Behavioral Neuroscience Reports, 2014Co-Authors: Matthew J. Hill, Enca Martin-rendon, Marc P Forrest, Derek J. BlakeAbstract:Genome wide association studies (GWAS) have revolutionized the study of complex diseases and have uncovered common genetic variants associated with an increased risk for major psychiatric disorders. A recently published schizophrenia GWAS replicated earlier findings implicating common variants in Transcription factor 4 (TCF4) as susceptibility loci for schizophrenia. By contrast, loss of function TCF4 mutations, although rare, cause Pitt-Hopkins syndrome (PTHS); a disorder characterized by intellectual disability (ID), developmental delay and behavioral abnormalities. TCF4 mutations have also been described in individuals with ID and non-syndromic neurodevelopmental disorders. TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that regulate gene expression at E-box-containing promoters and enhancers. Accordingly, TCF4 has an important role during brain development and can interact with a wide array of transcriptional regulators including some proneural factors. TCF4 may, therefore, participate in the transcriptional networks that regulate the maintenance and differentiation of distinct cell types during brain development. Here, we review the role of TCF4 variants in the context of several distinct brain disorders associated with impaired cognition.
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The emerging roles of TCF4 in disease and development
Trends in Molecular Medicine, 2014Co-Authors: Marc P Forrest, Matthew Hill, Andrew J. Quantock, Enca Martin-rendon, Derek J. BlakeAbstract:Genome-wide association studies have identified common variants in transcription factor 4 (TCF4) as susceptibility loci for schizophrenia, Fuchs’ endothelial corneal dystrophy, and primary sclerosing cholangitis. By contrast, rare TCF4 mutations cause Pitt–Hopkins syndrome, a disorder characterized by intellectual disability and developmental delay, and have also been described in patients with other neurodevelopmental disorders. TCF4 therefore sits at the nexus between common and rare disorders. TCF4 interacts with other basic helix–loop–helix proteins, forming transcriptional networks that regulate the differentiation of several distinct cell types. Here, we review the role of TCF4 in these seemingly diverse disorders and discuss recent data implicating TCF4 as an important regulator of neurodevelopment and epithelial–mesenchymal transition.
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Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation
PLoS ONE, 2013Co-Authors: Marc P Forrest, Enca Martin-rendon, Adrian James Waite, Derek J. BlakeAbstract:Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. 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. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown 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 (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) 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.
Elaine Fuchs - One of the best experts on this subject based on the ideXlab platform.
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In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators
Nature Cell Biology, 2014Co-Authors: Wen-hui Lien, Lisa Polak, Deyou Zheng, Elaine FuchsAbstract:Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin–TCF3/4–TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt–β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4–TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt–β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt–β-catenin levels rise, this balance is shifted and hair regeneration initiates. Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Fuchs and colleagues use a genome-wide survey to discover that Wnt effectors TCF3, TCF4 and Groucho (TLE) coordinately repress Wnt target genes. They find that although β-catenin is dispensable for HSFC viability and proliferation, it is essential to relieve this repression to initiate hair follicle fate during the hair regeneration cycle.
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in vivo transcriptional governance of hair follicle stem cells by canonical wnt regulators
Nature Cell Biology, 2014Co-Authors: Wen-hui Lien, Lisa Polak, Deyou Zheng, Elaine FuchsAbstract:Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin-TCF3/4-TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt-β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4-TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt-β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt-β-catenin levels rise, this balance is shifted and hair regeneration initiates. © 2014 Macmillan Publishers Limited. All rights reserved.
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Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3−β-catenin interaction
Development, 2012Co-Authors: Chun I Wu, Jackson A. Hoffman, Erin M. Ford, Hoang Nguyen, Elaine Fuchs, Bradley J. MerrillAbstract:The canonical Wnt/β-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef–β-catenin complexes. In contrast to β-catenin-dependent functions described for Tcf1, TCF4 and Lef1, the known embryonic functions for Tcf3 in mice, frogs and fish are consistent with β-catenin-independent repressor activity. In this study, we genetically define Tcf3–β-catenin functions in mice by generating a Tcf3ΔN knock-in mutation that specifically ablates Tcf3–β-catenin. Mouse embryos homozygous for the knock-in mutation (Tcf3ΔN/ΔN) progress through gastrulation without apparent defects, thus genetically proving that Tcf3 function during gastrulation is independent of β-catenin interaction. Tcf3ΔN/ΔN mice were not viable, and several post-gastrulation defects revealed the first in vivo functions of Tcf3–β-catenin interaction affecting limb development, vascular integrity, neural tube closure and eyelid closure. Interestingly, the etiology of defects indicated an indirect role for Tcf3–β-catenin in the activation of target genes. Tcf3 directly represses transcription of Lef1, which is stimulated by Wnt/β-catenin activity. These genetic data indicate that Tcf3–β-catenin is not necessary to activate target genes directly. Instead, our findings support the existence of a regulatory circuit whereby Wnt/β-catenin counteracts Tcf3 repression of Lef1, which subsequently activates target gene expression via Lef1–β-catenin complexes. We propose that the Tcf/Lef circuit model provides a mechanism downstream of β-catenin stability for controlling the strength of Wnt signaling activity during embryonic development.
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Tcf3 and TCF4 are essential for long-term homeostasis of skin epithelia
Nature Genetics, 2009Co-Authors: Hoang Nguyen, Bradley J. Merrill, Lisa Polak, Maria Nikolova, Michael Rendl, Timothy M Shaver, H Amalia Pasolli, Elaine FuchsAbstract:Single-layered embryonic skin either stratifies to form epidermis or responds to Wnt signaling (stabilized β-catenin) to form hair follicles. Postnatally, stem cells continue to differentially use Wnt signaling in long-term tissue homeostasis. We have discovered that embryonic progenitor cells and postnatal hair follicle stem cells coexpress Tcf3 and TCF4, which can act as transcriptional activators or repressors. Using loss-of-function studies and transcriptional analyses, we uncovered consequences to the absence of Tcf3 and TCF4 in skin that only partially overlap with those caused by β-catenin deficiency. We established roles for Tcf3 and TCF4 in long-term maintenance and wound repair of both epidermis and hair follicles, suggesting that Tcf proteins have both Wnt-dependent and Wnt-independent roles in lineage determination. Elaine Fuchs and colleagues present mice conditionally lacking Tcf3 and TCF4 in the skin and show that they play a role in long-term maintenance and wound repair of both epidermis and hair follicles.
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Tcf3 and TCF4 are essential for long-term homeostasis of skin epithelia
Nature Genetics, 2009Co-Authors: Hoang Nguyen, Bradley J. Merrill, Lisa Polak, Maria Nikolova, Michael Rendl, Timothy M Shaver, H Amalia Pasolli, Elaine FuchsAbstract:Single-layered embryonic skin either stratifies to form epidermis or responds to Wnt signaling (stabilized beta-catenin) to form hair follicles. Postnatally, stem cells continue to differentially use Wnt signaling in long-term tissue homeostasis. We have discovered that embryonic progenitor cells and postnatal hair follicle stem cells coexpress Tcf3 and TCF4, which can act as transcriptional activators or repressors. Using loss-of-function studies and transcriptional analyses, we uncovered consequences to the absence of Tcf3 and TCF4 in skin that only partially overlap with those caused by beta-catenin deficiency. We established roles for Tcf3 and TCF4 in long-term maintenance and wound repair of both epidermis and hair follicles, suggesting that Tcf proteins have both Wnt-dependent and Wnt-independent roles in lineage determination.
Tonis Timmusk - One of the best experts on this subject based on the ideXlab platform.
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The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A.
The Journal of Neuroscience, 2017Co-Authors: Mari Sepp, Stephanie Cerceo Page, Brady J. Maher, Mari Urb, Hanna Vihma, Kaja Nurm, Kaisa Roots, Anu Hark, Priit Pruunsild, Tonis TimmuskAbstract:Transcription factor 4 (TCF4 alias ITF2, E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability and schizophrenia. Here we show that TCF4-dependent transcription in cortical neurons, cultured from embryonic rats of both sexes, is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signalling. PKA directly phosphorylates TCF4 and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons as well as in the developing brain in vivo . We also demonstrate that Gadd45g (growth arrest and DNA damage inducible gamma) is a direct target of neuronal activity-induced TCF4-dependent transcriptional regulation and TCF4 missense variations identified in schizophrenia patients alter the transcriptional activity of TCF4 in neurons. Altogether, this study identifies a new role for TCF4 as a neuronal activity-regulated transcription factor, offering a novel perspective on the association of TCF4 with cognitive disorders. SIGNIFICANCE STATEMENT The importance of the basic helix-loop-helix transcription factor TCF4 in the nervous system is underlined by its association with common and rare cognitive disorders. In the current study we show that TCF4-controlled transcription in primary cortical neurons is induced by neuronal activity and protein kinase A. Our results support the hypotheses that dysregulation of neuronal activity-dependent signalling plays a significant part in the aetiology of neuropsychiatric and neurodevelopmental disorders.
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pitt hopkins syndrome associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant negative effects
Human Molecular Genetics, 2012Co-Authors: Mari Sepp, Priit Pruunsild, Tonis TimmuskAbstract:Transcription factor TCF4 (alias ITF2, SEF2 or E2-2) is a broadly expressed basic helix–loop–helix (bHLH) protein that functions as a homo- or heterodimer. Missense, nonsense, frame-shift and splice-site mutations as well as translocations and large deletions encompassing TCF4 gene cause Pitt –H opkins syndrome (PTHS), a rare developmental disorder characterized by severe motor and mental retardation, typical facial features and breathing anomalies. Irrespective of the mutation, TCF4 haploinsufficiency has been proposed as an underlying mechanism for PTHS. We have recently demonstrated that human TCF4 gene is transcribed using numerous 5 ′ exons. Here, we re-evaluated the impact of all the published PTHS-associated mutations, taking into account the diversity of TCF4 isoforms, and assessed how the reading frame elongating and missense mutations affect TCF4 functions. Our analysis revealed that not all deletions and truncating mutations in TCF4 result in complete loss-of-function and the impact of reading frame elongating and missense mutations ranges from subtle deficiencies to dominant-negative effects. We show that (i) missense mutations in TCF4 bHLH domain and the reading frame elongating mutation damage DNA-binding and transactivation ability in a manner dependent on dimer context (homodimer versus heterodimer with ASCL1 or NEUROD2); (ii) the elongating mutation and the missense mutation at the dimer interface of the HLH domain destabilize the protein; and (iii) missense mutations outside of the bHLH domain cause no major functional deficiencies. We conclude that different PTHS-associated mutations impair the functions of TCF4 by diverse mechanisms and to a varying extent, possibly contributing to the phenotypic variability of PTHS patients.
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functional diversity of human basic helix loop helix transcription factor TCF4 isoforms generated by alternative 5 exon usage and splicing
PLOS ONE, 2011Co-Authors: Mari Sepp, Kaja Kannike, Ave Eesmaa, Tonis TimmuskAbstract:Background Transcription factor 4 (TCF4 alias ITF2, E2-2, ME2 or SEF2) is a ubiquitous class A basic helix-loop-helix protein that binds to E-box DNA sequences (CANNTG). While involved in the development and functioning of many different cell types, recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and TCF4 haploinsufficiency is the cause of the Pitt-Hopkins mental retardation syndrome. However, the structure, expression and coding potential of the human TCF4 gene have not been described in detail. Principal Findings In the present study we used human tissue samples to characterize human TCF4 gene structure and TCF4 expression at mRNA and protein level. We report that although widely expressed, human TCF4 mRNA expression is particularly high in the brain. We demonstrate that usage of numerous 5′ exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. In addition, the diversity of isoforms is increased by alternative splicing of several internal exons. For functional characterization of TCF4 isoforms, we overexpressed individual isoforms in cultured human cells. Our analysis revealed that subcellular distribution of TCF4 isoforms is differentially regulated: Some isoforms contain a bipartite nuclear localization signal and are exclusively nuclear, whereas distribution of other isoforms relies on heterodimerization partners. Furthermore, the ability of different TCF4 isoforms to regulate E-box controlled reporter gene transcription is varied depending on whether one or both of the two TCF4 transcription activation domains are present in the protein. Both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination. Conclusions Altogether, in this study we have described the inter-tissue variability of TCF4 expression in human and provided evidence about the functional diversity of the alternative TCF4 protein isoforms.
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Functional Diversity of Human Basic Helix-Loop-Helix Transcription Factor TCF4 Isoforms Generated by Alternative 5′ Exon Usage and Splicing
PLoS ONE, 2011Co-Authors: Mari Sepp, Kaja Kannike, Ave Eesmaa, Mari Urb, Tonis TimmuskAbstract:Background Transcription factor 4 (TCF4 alias ITF2, E2-2, ME2 or SEF2) is a ubiquitous class A basic helix-loop-helix protein that binds to E-box DNA sequences (CANNTG). While involved in the development and functioning of many different cell types, recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and TCF4 haploinsufficiency is the cause of the Pitt-Hopkins mental retardation syndrome. However, the structure, expression and coding potential of the human TCF4 gene have not been described in detail. Principal Findings In the present study we used human tissue samples to characterize human TCF4 gene structure and TCF4 expression at mRNA and protein level. We report that although widely expressed, human TCF4 mRNA expression is particularly high in the brain. We demonstrate that usage of numerous 5′ exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. In addition, the diversity of isoforms is increased by alternative splicing of several internal exons. For functional characterization of TCF4 isoforms, we overexpressed individual isoforms in cultured human cells. Our analysis revealed that subcellular distribution of TCF4 isoforms is differentially regulated: Some isoforms contain a bipartite nuclear localization signal and are exclusively nuclear, whereas distribution of other isoforms relies on heterodimerization partners. Furthermore, the ability of different TCF4 isoforms to regulate E-box controlled reporter gene transcription is varied depending on whether one or both of the two TCF4 transcription activation domains are present in the protein. Both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination. Conclusions Altogether, in this study we have described the inter-tissue variability of TCF4 expression in human and provided evidence about the functional diversity of the alternative TCF4 protein isoforms.
Marc P Forrest - One of the best experts on this subject based on the ideXlab platform.
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Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia.
Science Advances, 2019Co-Authors: Abolfazl Doostparast Torshizi, Marc P Forrest, Chris Armoskus, Hanwen Zhang, Siwei Zhang, Tade Souaiaia, Oleg V. Evgrafov, James A. Knowles, Jubao Duan, Kai WangAbstract:Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified TCF4 as a top candidate MR that may be dysregulated in SCZ. We validated TCF4 as a MR through enrichment analysis of TCF4-binding sites in induced pluripotent stem cell (hiPSC)–derived neurons and in neuroblastoma cells. We further validated the predicted TCF4 targets by knocking down TCF4 in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed TCF4 gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that TCF4 may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.
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the psychiatric risk gene transcription factor 4 TCF4 regulates neurodevelopmental pathways associated with schizophrenia autism and intellectual disability
Schizophrenia Bulletin, 2018Co-Authors: Marc P Forrest, Matthew Hill, Adrian James Waite, David H Kavanagh, Katherine E Tansey, Derek J. BlakeAbstract:Background Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia. Conversely, rare damaging TCF4 mutations cause Pitt–Hopkins syndrome and have also been found in individuals with intellectual disability (ID) and autism spectrum disorder (ASD). Methods Chromatin immunoprecipitation and next generation sequencing were used to identify the genomic targets of TCF4. These data were integrated with expression, epigenetic and disease gene sets using a range of computational tools. Results We identify 10604 TCF4 binding sites in the genome that were assigned to 5437 genes. De novo motif enrichment found that most TCF4 binding sites contained at least one E-box (5′-CAtcTG). Approximately 77% of TCF4 binding sites overlapped with the H3K27ac histone modification for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction, and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P = 5.3 × 10−7), ASD (P = 2.5 × 10−4), and ID (P = 7.6 × 10−3) were also enriched among TCF4 targets. TCF4 binding sites were also found at other schizophrenia risk loci including the nicotinic acetylcholine receptor cluster, CHRNA5/CHRNA3/CHRNB4 and SETD1A. Conclusions These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include many genetic risk factors for common neurodevelopmental disorders.
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Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability
Current Behavioral Neuroscience Reports, 2014Co-Authors: Matthew J. Hill, Enca Martin-rendon, Marc P Forrest, Derek J. BlakeAbstract:Genome wide association studies (GWAS) have revolutionized the study of complex diseases and have uncovered common genetic variants associated with an increased risk for major psychiatric disorders. A recently published schizophrenia GWAS replicated earlier findings implicating common variants in Transcription factor 4 (TCF4) as susceptibility loci for schizophrenia. By contrast, loss of function TCF4 mutations, although rare, cause Pitt-Hopkins syndrome (PTHS); a disorder characterized by intellectual disability (ID), developmental delay and behavioral abnormalities. TCF4 mutations have also been described in individuals with ID and non-syndromic neurodevelopmental disorders. TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that regulate gene expression at E-box-containing promoters and enhancers. Accordingly, TCF4 has an important role during brain development and can interact with a wide array of transcriptional regulators including some proneural factors. TCF4 may, therefore, participate in the transcriptional networks that regulate the maintenance and differentiation of distinct cell types during brain development. Here, we review the role of TCF4 variants in the context of several distinct brain disorders associated with impaired cognition.
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The emerging roles of TCF4 in disease and development
Trends in Molecular Medicine, 2014Co-Authors: Marc P Forrest, Matthew Hill, Andrew J. Quantock, Enca Martin-rendon, Derek J. BlakeAbstract:Genome-wide association studies have identified common variants in transcription factor 4 (TCF4) as susceptibility loci for schizophrenia, Fuchs’ endothelial corneal dystrophy, and primary sclerosing cholangitis. By contrast, rare TCF4 mutations cause Pitt–Hopkins syndrome, a disorder characterized by intellectual disability and developmental delay, and have also been described in patients with other neurodevelopmental disorders. TCF4 therefore sits at the nexus between common and rare disorders. TCF4 interacts with other basic helix–loop–helix proteins, forming transcriptional networks that regulate the differentiation of several distinct cell types. Here, we review the role of TCF4 in these seemingly diverse disorders and discuss recent data implicating TCF4 as an important regulator of neurodevelopment and epithelial–mesenchymal transition.
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Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation
PLoS ONE, 2013Co-Authors: Marc P Forrest, Enca Martin-rendon, Adrian James Waite, Derek J. BlakeAbstract:Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. 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. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown 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 (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) 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.
Miguel L Allende - One of the best experts on this subject based on the ideXlab platform.
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Expression and splice variant analysis of the zebrafish TCF4 transcription factor
Mechanisms of Development, 2002Co-Authors: Rodrigo M Young, Ariel E Reyes, Miguel L AllendeAbstract:Wnt signalling has been implicated in antero-posterior patterning of the vertebrate embryonic body axis and in a number of other developmental processes. One of the downstream effectors of Wnt signalling is the β-catenin protein which complexes with members of the Lef/tcf transcription factor family. In the zebrafish, specification of the head has been shown to be dependent on the Tcf3 protein which acts as a repressor of the posteriorizing activity of Wnt (Nature 407 (2000) 913). Here, we report the cloning and expression pattern of the zebrafish TCF4 gene. In embryos, we find that the TCF4 gene is highly regulated at the level of RNA splicing such that the variant proteins that are produced contain or lack domains proposed to be essential in repression or activation of transcription. Expression of TCF4 mRNA is first detected in a graded fashion in the anterior brain and subsequently becomes restricted to the dorsal diencephalon and anterior midbrain. There is also transient expression in the anterior rhombomeres of the hindbrain and in the developing gut.
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Expression and splice variant analysis of the zebrafish TCF4 transcription factor.
Mechanisms of Development, 2002Co-Authors: Rodrigo M Young, Ariel E Reyes, Miguel L AllendeAbstract:Wnt signalling has been implicated in antero-posterior patterning of the vertebrate embryonic body axis and in a number of other developmental processes. One of the downstream effectors of Wnt signalling is the beta-catenin protein which complexes with members of the Lef/tcf transcription factor family. In the zebrafish, specification of the head has been shown to be dependent on the Tcf3 protein which acts as a repressor of the posteriorizing activity of Wnt (Nature 407 (2000) 913). Here, we report the cloning and expression pattern of the zebrafish TCF4 gene. In embryos, we find that the TCF4 gene is highly regulated at the level of RNA splicing such that the variant proteins that are produced contain or lack domains proposed to be essential in repression or activation of transcription. Expression of TCF4 mRNA is first detected in a graded fashion in the anterior brain and subsequently becomes restricted to the dorsal diencephalon and anterior midbrain. There is also transient expression in the anterior rhombomeres of the hindbrain and in the developing gut.
