Trait-associated noncoding variant regions affect TBX3 regulation and cardiac conduction
Open accessAbstract
Genome-wide association studies have implicated common genomic variants in the gene desert upstream of TBX3 in cardiac conduction velocity. Whether these noncoding variants affect expression of TBX3 or neighboring genes and how they affect cardiac conduction is not understood. Here, we use high-throughput STARR-seq to test the entire 1.3 Mb human and mouse TBX3 locus, including two cardiac conduction-associated variant regions, for regulatory function. We identified multiple accessible and functional regulatory DNA elements that harbor variants affecting their activity. Both variant regions drove gene expression in the cardiac conduction tissue in transgenic reporter mice. Genomic deletion from the mouse genome of one of the regions caused increased cardiac expression of only Tbx3, PR interval shortening and increased QRS duration. Combined, our findings address the mechanistic link between trait-associated variants in the gene desert, TBX3 regulation and cardiac conduction.
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The Tbx3-Venus reporter system is validated.
“To visualize the activity of the murine Tbx3 promoter at the protein level, we used a validated Tbx3-Venus (Tbx3tm1(Venus)Vmc) [11, 42–47] reporter system (Fig. 2a).”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [46]
The Results section (‘Identification of accessible regulatory elements within the murine Tbx3 locus’; page unavailable) uses Tbx3Venus/+ mice to isolate Tbx3+ cardiomyocytes, supporting that this is a reporter system used for that purpose. The cited passages do not describe a validation of the reporter, so they do not establish the ‘validated’ part of the claim. (LLM, conf=0.78)
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- Authors
- van Weerd, J. H., Mohan, R. A., van Duijvenboden, K., Hooijkaas, I. B., Wakker, V., Boukens, B. J., Barnett, P., & Christoffels, V. M.
- Affiliations
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam University Medical Centers (NL)
- Corresponding author
- Christoffels, Vincent M
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-07-16
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7365664
- OpenAlex
- W3043339430
- Cited by
- 12
- References
- 88
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 2
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Dutch Heart Foundation (CVON project CONCOR genes, COBRA3, 2016T047)
- Fondation Leducq (14CVD01)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- TBX3, cardiac conduction, non-coding variants, gene deserts, chromatin accessibility, STARR-seq, PR interval, QRS duration, cardiac conduction velocity, genotype-phenotype correlation, transgenic reporter mice, cardiac gene expression
- MeSH terms
- Animals, Arrhythmias, Cardiac, Heart Conduction System, Heart Rate, Humans, Mice, Transgenic, Gene Expression Regulation, Developmental, Polymorphism, Single Nucleotide, T-Box Domain Proteins, Genomics, Mice, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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