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

Genome-wide association studies have implicated common genomic variants in the gene desert upstream ofTBX3 in cardiac conduction velocity. Whether these noncoding variants affect expression ofTBX3 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 mouseTBX3 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 onlyTbx3, 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.
Source: eLife - Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research