Abstract 14227: A Pitx2-microRNA Pathway Functions in Inhibiting Susceptibility to Atrial Fibrillation

Background: Atrial fibrillation (AF) is the most common adult arrhythmia, but the molecular mechanisms underlying AF remain poorly understood. Genome wide association studies uncovered a major AF susceptibility locus on human chromosome 4q25 in close proximity to the Pitx2 homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in cardiac development, represses the sinoatrial node (SAN) program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesize that Pitx2 regulates microRNAs (miRs) to repress the SAN genetic program. microRNAs (miRs) are small non-coding RNAs that regulate gene expression post-transcriptionally. Methods and Results: Using miR-microarray and chromatin immuno-precipitation (ChIP) sequencing, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intra-cardiac electrical stimulation reveals that loss of miR-17-92 and miR-106b-25 increases susceptibility to AF, exhibitin...