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Trait-associated noncoding variant regions affect TBX3 regulation and cardiac conduction.


ABSTRACT: 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.

SUBMITTER: van Weerd JH 

PROVIDER: S-EPMC7365664 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Trait-associated noncoding variant regions affect <i>TBX3</i> regulation and cardiac conduction.

van Weerd Jan Hendrik JH   Mohan Rajiv A RA   van Duijvenboden Karel K   Hooijkaas Ingeborg B IB   Wakker Vincent V   Boukens Bastiaan J BJ   Barnett Phil P   Christoffels Vincent M VM  

eLife 20200716


Genome-wide association studies have implicated common genomic variants in the gene desert upstream of <i>TBX3</i> in cardiac conduction velocity. Whether these noncoding variants affect expression of <i>TBX3</i> 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 <i>TBX3</i> locus, including two cardiac conduction-associated variant regions, for regulatory function. We identified multiple  ...[more]

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