Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (25), p.9181-9186
• Main Authors: Wang, Jun, Bai, Yan, Li, Na, Ye, Wenduo, Zhang, Min, Greene, Stephanie B., Tao, Ye, Chen, Yiping, Wehrens, Xander H. T., Martin, James F.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Atrial fibrillation; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Biological Sciences; Cardiac arrhythmia; Developmental biology; Dysrhythmias; Genes; Genetic Predisposition to Disease; Heart; Homeobox Protein PITX2; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human genetics; Humans; Mice; Mice, Knockout; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Myocardium; Polymerase chain reaction; Ribonucleic acid; RNA; Rodents; Sinoatrial Node - metabolism; Sinoatrial Node - pathology; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Telemetry; Transcription Factors - genetics; Transcription Factors - metabolism; Untranslated regions
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405411111

The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2 , a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25 . Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3 , that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility.