The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters
| Autor: | Kaja Nurm, Jürgen Tuvikene, Tõnis Timmusk, Mari Sepp, Alex Sirp, Kristian Leite |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Corneal diseases Bipolar disorder Molecular biology Transcriptional regulatory elements lcsh:Medicine Biology Molecular neuroscience Article 03 medical and health sciences Exon Transactivation Reporter genes 0302 clinical medicine Transcription Factor 4 Humans Promoter Regions Genetic lcsh:Science Gene Genetics Multidisciplinary Alternative splicing Fuchs' Endothelial Dystrophy lcsh:R Intron Promoter RNA sequencing TCF4 Gene regulation Alternative Splicing 030104 developmental biology Mechanisms of disease Reverse transcription polymerase chain reaction Microsatellite instability lcsh:Q Gene expression Trinucleotide repeat expansion Trinucleotide Repeat Expansion 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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