TY - JOUR
T1 - Trait-associated noncoding variant regions affect TBX3 regulation and cardiac conduction
AU - van Weerd, Jan Hendrik
AU - Mohan, Rajiv A.
AU - van Duijvenboden, Karel
AU - Hooijkaas, Ingeborg B.
AU - Wakker, Vincent
AU - Boukens, Bastiaan J.
AU - Barnett, Phil
AU - Christoffels, Vincent M.
PY - 2020/7/16
Y1 - 2020/7/16
N2 - 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.
AB - 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.
KW - CRISPR/Cas9
KW - E. coli
KW - SNP
KW - atrioventricular conduction system
KW - chromosomes
KW - enhancer
KW - epigenomics
KW - gene expression
KW - genetics
KW - genomics
KW - mouse
KW - transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85088155057&partnerID=8YFLogxK
U2 - https://doi.org/10.7554/eLife.56697
DO - https://doi.org/10.7554/eLife.56697
M3 - Article
C2 - 32672536
SN - 2050-084X
VL - 9
SP - 1
EP - 26
JO - eLife
JF - eLife
M1 - e56697
ER -