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Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation
- Source :
- Proceedings of the National Academy of Sciences. 111:9181-9186
- Publication Year :
- 2014
- Publisher :
- Proceedings of the National Academy of Sciences, 2014.
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
Biology
Mice
Internal medicine
Atrial Fibrillation
microRNA
medicine
Animals
Humans
Genetic Predisposition to Disease
Nodal signaling pathway
Transcription factor
Sinoatrial Node
Homeodomain Proteins
Mice, Knockout
Multidisciplinary
PITX2
Sinoatrial node
Cardiac arrhythmia
Atrial fibrillation
Biological Sciences
medicine.disease
Cell biology
MicroRNAs
medicine.anatomical_structure
Endocrinology
Homeobox
T-Box Domain Proteins
Transcription Factors
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 111
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c781e47888835046c1ef2890091bd2c9