Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay.
The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.2 (Cx30.2, also known as Gjd3) gene, which encodes a gap junction protein required for normal atrioventricular (AV) delay in mice, is necessary and sufficient to direct expression to the developing AV conduction system (AVCS). Moreover, we show that this enhancer requires Tbx5 and Gata4 for proper expression in the conduction system, and Gata4(+/-) mice have short PR intervals indicative of accelerated AV conduction. Thus, our results implicate Gata4 in conduction system function and provide a clearer understanding of the transcriptional pathways that impact normal AV delay.
Munshi
Nikhil V
NV
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
McAnally
John
J
Bezprozvannaya
Svetlana
S
Berry
Jeff M
JM
Richardson
James A
JA
Hill
Joseph A
JA
Olson
Eric N
EN
D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D017630:Connexins / Q000235:genetics*; D004562:Electrocardiography; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006329:Heart Conduction System / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020825:T-Box Domain Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes
D017630:Connexins; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C510757:connexin 30.2, mouse