The emerging roles of TCF4 in disease and development

Forrest, Marc P.; Hill, Matthew; Quantock, Andrew J.; Martin‐Rendon, Enca; Blake, Derek J.

doi:10.1016/j.molmed.2014.01.010

Cited by 144 publications

(122 citation statements)

References 114 publications

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“…[47]). These data provide further support for the notion that TCF4 regulates the expression of genes that direct neuronal differentiation and development [48]. …”

Section: Resultssupporting

confidence: 76%

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

et al. 2017

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Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.

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“…[47]). These data provide further support for the notion that TCF4 regulates the expression of genes that direct neuronal differentiation and development [48]. …”

Section: Resultssupporting

confidence: 76%

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

et al. 2017

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“…Finally, we got five SNPs (rs1261134, rs9320010, rs7235757, rs2958182, and rs1452787) of TCF4 which were analyzed in previous studies [Li et al, 2010;Favis et al, 2011;Wirgenes et al, 2012;Ellinghaus et al, 2013;Zhu et al, 2013;Forrest et al, 2014].…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

“…Although the exact etiology and mechanism of SCZ are not well understood, the heritability of this disease has been estimated to be as high as 80% from family, adoption and twin studies, suggesting that genetic factors may play an important role in the pathophysiology of SCZ [Cardno and Gottesman, 2000;Craddock et al, 2005;Aberg et al, 2013]. It has been confirmed that the transcription factor 4 (TCF4) which is located on chromosome 18q21.1 and encoded a basic helix-loophelix transcription factor [Forrest et al, 2014] was one of the most prominent susceptibility genes for SCZ [Stefansson et al, 2009]. The gene comprises 41 exons and spans 437 kb.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of the TCF4 gene are associated with the risk of schizophrenia in the Han Chinese

Chen

Wang

et al. 2016

American J of Med Genetics Pt B

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Schizophrenia (SCZ) is a complex and severe mental disorder with highly heritability (80%). Several large genome-wide association studies have identified that the transcription factor 4 (TCF4) polymorphisms were strongly associated with SCZ. Therefore, the present study was to replicate the potential relationships between the TCF4 polymorphisms and SCZ. Furthermore, the study also investigated whether other variants were associated with SCZ in the Han Chinese. We conducted a case-control study including 499 patients and 500 healthy controls. Five SNPs were successfully genotyped and evaluated the association with SCZ by using χ test and genetic model analysis. We found that the genotype "AG" of rs9320010 and "GA" of rs7235757 decreased SCZ risk (OR = 0.70, 95%CI = 0.50-0.99, P = 0.041; OR = 0.69, 95%CI = 0.49-0.97, P = 0.034, respectively). In the genetic model analysis, we also observed that the allele "A" of rs9320010 and "G" of rs7235757 were inversely related with the risk of SCZ in the dominant model (OR = 0.72, 95%CI = 0.52-0.98, P = 0.039; OR = 0.69, 95%CI = 0.50-0.96, P = 0.025, respectively). Further interaction and stratification analysis suggested that rs1452787 was notably correlated with increased SCZ risk in males (OR = 2.77, 95%CI = 1.43-5.35, P = 0.002). Our study indicated that rs9320010, rs7235757, and rs1452787 were prominently associated with SCZ. Further studies are required to verify our findings and focus on determining the biological functions of the SNPs. © 2016 Wiley Periodicals, Inc.

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“…In contrast, some B-HLHs are involved in specifying cell identity and differentiation, like ASCL1, ATOH1, NEUROD1, NEUROG, TCF4 (E2A), TCF3 (E2–2, ITF2), and TCF12 (HEB) and bind to non-CG dinucleotide containing E-Box motifs like CAG∣GTG or CAG∣CTG that localize outside of CGIs 20 . TCF4 binds E-Box motifs both as a homodimer and a heterodimer with various tissue specific B-HLH proteins to form transcriptional networks that regulate cellular differentiation of many cell types 21 . Aberrant expression and/or mutations in TCF4 can cause abnormal brain development leading to neurodevelopmental disorders such as Pitt-Hopkins syndrome, schizophrenia, Fuchs’ corneal endothelial dystrophy, and primary sclerosing cholangitis 21, 22 .…”

Section: Introductionmentioning

confidence: 99%

5-Hydroxymethylcytosine in E-box motifs ACAT|GTG and ACAC|GTG increases DNA-binding of the B-HLH transcription factor TCF4

Khund-Sayeed

Holzberg

et al. 2016

Integr. Biol.

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We evaluated DNA binding of the B-HLH family members TCF4 and USF1 using protein binding microarrays (PBMs) containing double-stranded DNA probes with cytosine on both strands or 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) on one DNA strand and cytosine on the second strand. TCF4 preferentially bound the E-Box motif (CAN∣NTG) with strongest binding to the 8-mer CAG∣GTGGT. 5mC uniformly decreases DNA binding of both TCF4 and USF1. The bulkier 5hmC also inhibited USF1 binding to DNA. In contrast, 5hmC dramatically enhanced TCF4 binding to E-Box motifs ACAT∣GTG and ACAC∣GTG, being better bound than any 8-mer containing cytosine. Examination of x-ray structures of the closely related TCF3 and USF1 bound to DNA suggests TCF3 can undergo a conformational shift to preferentially bind to 5hmC while the USF1 basic region is bulkier and rigid precluding a conformation shift to bind 5hmC. These results greatly expand the regulatory DNA sequence landscape bound by TCF4. Cytosine methylation outside CG dinucleotide has recently been identified in stem cells and the brain. To explore potential changes in sequence-specific DNA binding of transcription factors, we use Agilent DNA microarrays and did the double stranding reaction with 5mC or 5hmC. Using this technical innovation we explored DNA binding specificity of two helix-loop-helix proteins. For USF1, these modifications inhibited binding, while for TCF4, new sequences were bound. This innovation of DNA microarray slides opens up new possibilities to explore how modification of DNA alters transcription factor binding to mediate changes of biological importance.

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The emerging roles of TCF4 in disease and development

Cited by 144 publications

References 114 publications

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

Polymorphisms of the TCF4 gene are associated with the risk of schizophrenia in the Han Chinese

5-Hydroxymethylcytosine in E-box motifs ACAT|GTG and ACAC|GTG increases DNA-binding of the B-HLH transcription factor TCF4

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