<i>Pitx2</i>
            , an Atrial Fibrillation Predisposition Gene, Directly Regulates Ion Transport and Intercalated Disc Genes

Tao, Ye; Zhang, Min; Li, Lele; Bai, Yan; Zhou, Yuefang; Moon, Anne M.; Kaminski, Henry J.; Martin, James F.

doi:10.1161/circgenetics.113.000259

Cited by 111 publications

(112 citation statements)

References 50 publications

(65 reference statements)

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“…ChIP-Seq analysis using chromatin from adult mouse heart of the Pitx2 Flag allele (GEO accession no. GSE50401) (18) revealed that Pitx2 directly binds conserved chromatin upstream of miR-17-92 and miR-106b-25 (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…To gain insight into miRs involved in AF pathogenesis, we performed miR expression profiling using hearts from Pitx2 null/null mutant and wild type, and ChIP-sequencing (ChIP-Seq) using hearts from the Pitx2-Flag allele (16,18), which express Pitx2 with a C-terminal Flag epitope tag ( Fig. 1 A and C).…”

Section: Resultsmentioning

confidence: 99%

“…E13.5 hearts were collected from Pitx2 Flag allele and followed by ChIP analysis as previously described (16), and DNA obtained from ChIP were used for real-time PCR to quantify enrichment. ChIP-Seq was performed using 3-mo-old mouse whole hearts of Pitx2 Flag allele, and data are available through the Gene Expression Omnibus (GEO) data repository under accession number GSE50401 (18). For ChIP-Seq analysis, Ion torrent PGM reads were aligned to the mm9 (NCBI Build 37) assembly using Torrent Suite (2.0.1) Ion-alignment (2.0.3-1).…”

Section: Methodsmentioning

confidence: 99%

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

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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106

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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. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

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“…63 In the postnatal atria, PTX2 also plays important role in the integrity of the intercalated discs, and knockout mice demonstrate evidence for SND. 64 Thus PTX2 has generated considerable interest as having a role in AF and possibly SND although evidence regarding the expression of PTX2 and its target genes in AF is still missing.…”

Section: Genetic Mutations Common To Snd and Afmentioning

confidence: 99%

Sinus Node and Atrial Arrhythmias

2016

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Sinus node dysfunction (SND) and atrial arrhythmias frequently coexist and interact to initiate and perpetuate each other. Atrial arrhythmias are present in 40% to 70% of patients at the time of diagnosis of SND.1,2 However, the complex relationship between the 2 remains ill defined. The documented degenerative changes in atrial myocardial structure relating to SND are primarily right atrial. Yet, the majority of triggers and substrates for atrial fibrillation (AF) originate from the left atrium. Although progressive biatrial fibrosis is a feature in patients with structural heart disease and in senescence, paroxysmal AF that occurs in patients with no structural heart disease may have a different pathophysiology. SND associated with this latter condition is likely to be primarily a result of electric remodeling and potentially reversible. The time course of the progression of SND and AF 3 and their individual clinical manifestations also vary depending on the underlying pathology. The purpose of this review is to summarize the state of our knowledge of sinus node (SN) function in both health and disease, and to understand the complex relationship between SN disease and atrial arrhythmias. Structure and Functional Components of the Sinus NodeIn the adult human heart, the SN is a crescent-shaped structure 1 to 2 cm long and 0.5 cm wide that lies at the junction of the superior vena cava with the right atrium and lies along the sulcus terminalis. The node itself is composed of clusters of pacemaker myocytes arranged in parallel rows with short digitations that frequently anastomose with the surrounding atrial tissue. The specialized pacemaker cells are interspersed with nerves and capillaries and scaffolded by dense connective tissue to form the SN pacemaker complex. The caudal portion fragments to merge with the atrial myocardium. The lack of a distinct encapsulation and the radiating sinoatrial connections explains the lack of a single breakthrough of the sinus impulse. The position of the leading pacemaker site shifts within the node and varies with sympathetic and vagal stimulation. 3The SN pacemaker cells are interspersed with interstitial collagen that varies in extent as a function of older age. 4 Collagen content increases from 24% in the infant to 70% in the adult heart.5 The fibrous matrix with surrounding fatty insulation of the SN together with distinct electrophysiological properties (see below) provides insulation and prevents the depression of pacemaker automaticity from the hyperpolarizing electric load of the surrounding atrial myocardium. 6 Multiple currents are involved in the activation of the SN. The predominant inward current in the center of the node is I CaL . Action potentials with slow upstrokes initiated in the center spreads peripherally and into the musculature of the terminal crest. However, in the periphery of the node, I Na is operative and is necessary for providing sufficient inward current to depolarize the larger mass of atrial tissue. Delayed rectifier potassium currents facili...

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“…[3][4][5] Reducing PITX2 levels alters the expression of several relevant left atrial genes, 6 and the effects of PITX2 on gene regulation are partially mediated by the miR-17 to miR-92 complex. 7 Preliminary analyses suggest that PITX2 regulates ion channel genes in the left atrium, 5,8 underpinning the observation that reduced atrial PITX2 levels shorten the atrial action potential and cause membrane potential depolarization. 3,9 On the basis of these insights and the impact of gene variants on chromosome 4q25 for AF, the genetic predisposition to AF has been identified as a promising candidate to develop personalized approaches to AF management.…”

Section: See Article By Gore-panter Et Almentioning

confidence: 99%