scholarly journals The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alex Sirp ◽  
Kristian Leite ◽  
Jürgen Tuvikene ◽  
Kaja Nurm ◽  
Mari Sepp ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Protein Isoforms ◽  
Compensatory Mechanism ◽  
Alternative Promoters ◽  
Rna Seq ◽  
Increased Risk ◽  
Specific Manner ◽  
Transcription Factor 4

Abstract The CTG trinucleotide repeat (TNR) expansion in Transcription factor 4 (TCF4) intron 3 is the main cause of Fuchs’ endothelial corneal dystrophy (FECD) and may confer an increased risk of developing bipolar disorder (BD). Usage of alternative 5′ exons for transcribing the human TCF4 gene results in numerous TCF4 transcripts which encode for at least 18 N-terminally different protein isoforms that vary in their function and transactivation capability. Here we studied the TCF4 region containing the CTG TNR and characterized the transcription initiation sites of the nearby downstream 5′ exons 4a, 4b and 4c. We demonstrate that these exons are linked to alternative promoters and show that the CTG TNR expansion decreases the activity of the nearby downstream TCF4 promoters in primary cultured neurons. We confirm this finding using two RNA sequencing (RNA-seq) datasets of corneal endothelium from FECD patients with expanded CTG TNR in the TCF4 gene. Furthermore, we report an increase in the expression of various other TCF4 transcripts in FECD, possibly indicating a compensatory mechanism. We conclude that the CTG TNR affects TCF4 expression in a transcript-specific manner both in neurons and in the cornea.

scholarly journals Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy

Eye ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 880-885 ◽  
Author(s):  
Naoki Okumura ◽  
Vilavun Puangsricharern ◽  
Raina Jindasak ◽  
Noriko Koizumi ◽  
Yuya Komori ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Transcription Factor 4

scholarly journals A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49083 ◽  
Author(s):  
Eric D. Wieben ◽  
Ross A. Aleff ◽  
Nirubol Tosakulwong ◽  
Malinda L. Butz ◽  
W. Edward Highsmith ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Transcription Factor 4

scholarly journals Lower Fractions of TCF4 Transcripts Spanning over the CTG18.1 Trinucleotide Repeat in Human Corneal Endothelium

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2006
Author(s):  
Ida Maria Westin ◽  
Andreas Viberg ◽  
Berit Byström ◽  
Irina Golovleva
Keyword(s):  
Endothelial Cells ◽  
Corneal Endothelium ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Corneal Dystrophy ◽  
Digital Pcr ◽  
Corneal Endothelial Cells ◽  
Transcription Start Sites ◽  
Gradual Loss ◽  
Transcription Factor 4

Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral disease of the cornea caused by gradual loss of corneal endothelial cells. Late-onset FECD is strongly associated with the CTG18.1 trinucleotide repeat expansion in the Transcription Factor 4 gene (TCF4), which forms RNA nuclear foci in corneal endothelial cells. To date, 46 RefSeq transcripts of TCF4 are annotated by the National Center of Biotechnology information (NCBI), however the effect of the CTG18.1 expansion on expression of alternative TCF4 transcripts is not completely understood. To investigate this, we used droplet digital PCR for quantification of TCF4 transcripts spanning over the CTG18.1 and transcripts with transcription start sites immediately downstream of the CTG18.1. TCF4 expression was analysed in corneal endothelium and in whole blood of FECD patients with and without CTG18.1 expansion, in non-FECD controls without CTG18.1 expansion, and in five additional control tissues. Subtle changes in transcription levels in groups of TCF4 transcripts were detected. In corneal endothelium, we found a lower fraction of transcripts spanning over the CTG18.1 tract compared to all other tissues investigated.

scholarly journals Impact of TCF4 Repeat Number on Resolution of Corneal Edema after Descemet’s Stripping Only in Fuchs Dystrophy: A Pilot Study

Vision ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 47
Author(s):  
Natasha Spiteri ◽  
Nino Hirnschall ◽  
Katherine van Bysterveldt ◽  
Alec Lin Hou ◽  
Gregory Moloney ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Corneal Edema ◽  
Corneal Dystrophy ◽  
Partial Least Square ◽  
Least Square ◽  
Partial Least Square Regression ◽  
Ctg Repeats ◽  
Increased Risk ◽  
Transcription Factor 4 ◽  
Allele Repeat

Purpose: To investigate whether Fuchs endothelial corneal dystrophy (FECD) genotype, specifically transcription factor 4 (TCF4) CTG triplet repeat “load” predicts time to clearance following Descemet’s Stripping Only (DSO). Methods: This prospective, interventional trial was conducted on consecutive FECD patients undergoing DSO. Genetic analysis using patients’ saliva was performed to assess the extent of CTG expansion using short tandem repeat analysis, corroborated gel electrophoresis and Sanger sequencing. Polymerase chain reaction and bidirectional Sanger sequencing was undertaken. Partial least square regression and logistic regression modelling was used to evaluate the predictive power of TCF4 repeats on corneal clearance. Results: Of 11 eyes of 11 patients, 8 showed complete corneal clearance. For these 8 patients, mean TCF4 allele repeat was 24.8 (SD: 23.7, range: 11–63) and 63.4 (SD: 30.3; range: 11–97), respectively. In total, 9/11 (81.8%) had expanded CTG repeats (>40) in one allele. In cases with an allele repeat ≥80, there was a significantly increased risk of corneal non-clearance (odds ratio 18.2, p = 0.009). Conclusion: Whilst it was not possible to predict time to corneal clearance based on CTG repeats, there is a significant correlation between allele repeats and achievement of corneal clearance.

scholarly journals Towards Clinical Trials in Fuchs Endothelial Corneal Dystrophy: Classification and Outcome Measures—The Bowman Club Lecture 2019

2019 ◽  
Vol 4 (1) ◽  
pp. e000321 ◽  
Author(s):  
Sanjay V Patel
Keyword(s):  
Clinical Trials ◽  
Outcome Measures ◽  
Trinucleotide Repeat ◽  
Clinical Investigation ◽  
Corneal Dystrophy ◽  
Underlying Disease ◽  
Surgical Removal ◽  
Disease Mechanisms ◽  
Transcription Factor 4 ◽  
Careful Thought

The surgical treatment of Fuchs endothelial corneal dystrophy (FECD) has advanced dramatically over the last two decades. Penetrating keratoplasty has been superseded by various iterations of endothelial keratoplasty, and currently, surgical removal of host Descemet membrane without keratoplasty is being investigated. These surgical advances have been accompanied by significant improvement of our understanding of the underlying disease mechanisms, not least the discovery that FECD in western populations is predominantly an intronic trinucleotide repeat expansion disorder in the transcription factor 4 gene that results in RNA toxicity and mis-splicing. Understanding the disease mechanisms augurs well for developing targeted molecular medical therapies, which will require careful clinical investigation through trials to prove their efficacy and safety. As the field advances towards clinical trials, investigators should carefully define the disease state being treated and consider the options for outcome measures relevant to the type of intervention. FECD, and the outcomes of interventions to treat the disease, can be measured in terms of corneal morphology, corneal function and clinical impact. Standardising the approach for defining FECD and careful thought about the outcomes of intervention that are reported will help make the results of future trials for FECD applicable in clinical practice.

scholarly journals Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs’ Endothelial Corneal Dystrophy

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0210996 ◽  
Author(s):  
Yu Qiang Soh ◽  
Gary Peh Swee Lim ◽  
Hla Myint Htoon ◽  
Xin Gong ◽  
V. Vinod Mootha ◽  
...  
Keyword(s):  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Clinical Progression ◽  
Trinucleotide Repeat Expansion

scholarly journals Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mathys Grapotte ◽  
Manu Saraswat ◽  
Chloé Bessière ◽  
Christophe Menichelli ◽  
Jordan A. Ramilowski ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Tandem Repeats ◽  
Specific Gene ◽  
Rna Seq ◽  
Transcription Start Sites ◽  
Long Read ◽  
Cap Analysis ◽  
Dna Tandem Repeats ◽  
Short Tandem ◽  
Str Polymorphism

AbstractUsing the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.

scholarly journals Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

2020 ◽  
Author(s):  
Mathys Grapotte ◽  
Manu Saraswat ◽  
Chloé Bessière ◽  
Christophe Menichelli ◽  
Jordan A. Ramilowski ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Tandem Repeats ◽  
Specific Gene ◽  
Rna Seq ◽  
Transcription Start Sites ◽  
Dna Motif ◽  
Long Reads ◽  
Cap Analysis ◽  
Dna Tandem Repeats ◽  
Short Tandem

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of Transcription Start Sites (TSSs) in several species. Strikingly, ~ 72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probed these unassigned TSSs and showed that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we developed Cap Trap RNA-seq, a technology which combines cap trapping and long reads MinION sequencing. We trained sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveiled the importance of STR surrounding sequences not only to distinguish STR classes, as defined by the repeated DNA motif, one from each other, but also to predict their transcription. Excitingly, our models predicted that genetic variants linked to human diseases affect STR-associated transcription and correspond precisely to the key positions identified by our models to predict transcription. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.

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