title: Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.
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.
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics,Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118.
authors.forename: Wenduo
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Molecular Physiology and Biophysics,Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030; and.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Greene
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular Physiology and Biophysics,Department of Medicine, Division of Cardiology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Department of Molecular Physiology and Biophysics,Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030; andTexas Heart Institute, Houston, TX 77030;Program in Developmental Biology, and jfmartin@bcm.edu.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C575895:MIRN17-92 microRNA, mouse; C543896:Mirn106 microRNA, mouse; C484663:Shox2 protein, mouse; C491460:Tbx3 protein, mouse
keywords: irregular heart rate; mouse genetics; single nucleotide variant