ArticleOrphanet journal of rare diseases2021
Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation.
Article in Orphanet journal of rare diseases, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 18 citations in OpenAlex.
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Language Modelling Techniques for Analysing the Impact of Human Genetic Variation.Bioinformatics and biology insights · 2025Review
- Decoding Non-coding Variants: Recent Approaches to Studying Their Role in Gene Regulation and Human Diseases.Frontiers in bioscience (Scholar edition) · 2024Review
- Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.Pediatric research · 2024Article
- Establishment of the Myeloid TBX-Code Reveals Aberrant Expression of T-Box Gene TBX1 in Chronic Myeloid Leukemia.International journal of molecular sciences · 2023Article
- Prioritizing cardiovascular disease-associated variants altering NKX2-5 and TBX5 binding through an integrative computational approach.The Journal of biological chemistry · 2023Article
- An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract.Circulation · 2023Article
- Disease-associated non-coding variants alter NKX2-5 DNA-binding affinity.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
- Evaluating High-Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses.Journal of the American Heart Association · 2023Article
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9 authors at 1 institution in 1 country.
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Abstract
backgroundTBX1 (T-box transcription factor 1) is a major candidate gene that likely contributes to the etiology of velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of TBX1.
methodsDifferent TBX1 promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a cis-regulatory element within the TBX1 promoter region and its trans-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the cis-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of TBX1.
resultsWe identified a cis-regulatory element within intron 1 of TBX1 that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of TBX1 by directly binding with its GATA cis-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C > G, NC_000022.11:g.19756845C > T, and NC_000022.11:g. 19756902G > T) in the non-coding cis-regulatory element of TBX1. Luciferase assays showed that all 3 variants led to reduced transcription of TBX1 when incubated with GATA6.
conclusionsOur findings showed that TBX1 might be a direct transcriptional target of GATA6, and variants in the non-coding cis-regulatory element of TBX1 disrupted GATA6-mediated transactivation.
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