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

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) linked variants in a gene desert upstream of TBX3 to cardiac conduction velocity.
• The functional impact of these noncoding variants on TBX3 expression and cardiac function remains unclear.

Purpose of the Study:

• To investigate the regulatory function of the TBX3 locus and the impact of associated variants on gene expression and cardiac conduction.
• To elucidate the mechanistic link between GWAS-identified variants and cardiac electrophysiology.

Main Methods:

• High-throughput STARR-seq was employed to assess regulatory activity across the 1.3 Mb human and mouse TBX3 locus.
• Transgenic reporter mice were used to evaluate the function of identified regulatory elements in cardiac tissue.
• Genomic deletion of a regulatory region in mice was performed to assess its in vivo effect.

Main Results:

• Multiple accessible and functional regulatory DNA elements were identified within the TBX3 locus, some harboring variants that alter their activity.
• Both variant-harboring regions demonstrated gene-driving activity in cardiac conduction tissue in transgenic models.
• Deletion of one regulatory region in mice led to increased cardiac TBX3 expression, PR interval shortening, and increased QRS duration.

Conclusions:

• The study identifies functional regulatory elements in the TBX3 gene desert, linking noncoding variants to TBX3 regulation.
• These findings establish a mechanistic connection between genetic variants, TBX3 expression, and cardiac conduction abnormalities.