microRNA in cardiac arrhythmias

microRNAs (miRs) are small endogenous non-coding RNAs that function in biologic processes primarily via post-transcriptional gene silencing. Previous genome-wide association studies and mouse studies indicated homeobox gene Pitx2 as a predisposition gene of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. To identify miRs function in AF, we performed miR expression profiling and ChIP-sequencing (ChIP-Seq) using different Pitx2 alleles. We found that Pitx2 positively regulates miR-17-92 and its homologous cluster miR-106b-25. Both miR-17-92 and miR-106b-25 deficient mice had pacing-induced AF under programmed stimulation. Electrocardiogram telemetry further revealed that mice with miR-17-92 cardiac-specific conditional knockout (CKO) developed prolonged PR intervals whereas mice with miR-17-92 cardiac-specific CKO and miR-106b-25 heterozygosity developed sinoatrial node dysfunction(SND). Both arrhythmias are AF risk factors in humans. Importantly, miR-17-92 and miR-106b-25 directly r...