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

ELife
Jan Hendrik van WeerdVincent M Christoffels

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.

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Citations

Jul 3, 2021·Journal of Cardiovascular Development and Disease·Mathilde R RivaudBastiaan J Boukens
Aug 13, 2021·Nature Reviews. Cardiology·Chukwuemeka G Anene-NzeluRoger S Y Foo

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Datasets Mentioned

BETA
GM12878
GSE121464
GM3500

Methods Mentioned

BETA
human Hi-C
ChIP-seq
Hi-C
transfections
transfection
Fluorescence
PCR
genotyping
transgenics
in vitro transcription

Software Mentioned

mergeBED
bamCoverage
HOMER
BEDTools
EMERGE
bamCompare
Genomic Evolutionary Rate Profiling
ZiFit Targeter
UCSC genome browser
BWA

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