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Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [ChIP-seq]

ABSTRACT: Genome-wide association studies (GWAS) have found that increased risk for atrial fibrillation (AF), the most common type of arrhythmia in humans, is associated with non-coding sequence variants located in proximity to the PITX2 homeobox gene. Using cardiomyocyte-specific epigenomic and comparative genomic analyses, we identified two AF-associated enhancers neighboring PITX2 with varying degrees of conservation in mice. Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9 mediated deletion of a 20 kb long topologically engaged enhancer lead to reduced Pitx2c transcription and AF predisposition. Allele-specific ChIP-seq and CUT&RUN experiments showed that long-range interaction of this AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Moreover, long-range looping was mediated by CTCF, as the genetic disruption of an intronic CTCF binding site caused decreased Pitx2c cardiac expression, AF predisposition, and reduced active chromatin marks on Pitx2. Our findings reveal that AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2

ORGANISM(S): Mus musculus

PROVIDER: GSE138528 | GEO | 2019/10/08

REPOSITORIES: GEO

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Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [RNA-seq]

Project description:Genome-wide association studies (GWAS) have found that increased risk for atrial fibrillation (AF), the most common type of arrhythmia in humans, is associated with non-coding sequence variants located in proximity to the PITX2 homeobox gene. Using cardiomyocyte-specific epigenomic and comparative genomic analyses, we identified two AF-associated enhancers neighboring PITX2 with varying degrees of conservation in mice. Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9 mediated deletion of a 20 kb long topologically engaged enhancer lead to reduced Pitx2c transcription and AF predisposition. Allele-specific ChIP-seq and CUT&RUN experiments showed that long-range interaction of this AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Moreover, long-range looping was mediated by CTCF, as the genetic disruption of an intronic CTCF binding site caused decreased Pitx2c cardiac expression, AF predisposition, and reduced active chromatin marks on Pitx2. Our findings reveal that AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2

2019-10-08 | GSE138529 | GEO

Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation

Project description:Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation

| PRJNA576253 | ENA

Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [RNA-seq]

Project description:Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [RNA-seq]

| PRJNA576255 | ENA

Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [ChIP-seq]

Project description:Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [ChIP-seq]

| PRJNA576256 | ENA

PANCR, the PITX2 adjacent noncoding RNA, is specifically expressed in human left atria and regulates PITX2c expression

Project description:Purpose: Common genetic variation at chromosome 4q25 lead to the strongest locus associated with atrial fibrillation (AF), the most frequent arrhythmia. The mechanism of association is currently unknown. We recently have identified a novel noncoding RNA expressed in the left atria. To determine the potential functional roles of the LNCRNA adjacent to PITX2 (PANCR) via knockdown in cardiomyocytes Methods and Results: H9 differentiated cardiomyocytes were treated with siRNA targeting PANCR and PITX2c and a scrambled control in triplicate. RNA and small RNA extracted and sent for sequencing. Approximately 50 million read fragments mapped to the transcriptome using STAR aligner to hg19 and fragments counted with htseq. EdgeR was used to quantify the differences between treatment groups. There were significant changes upon knocking down PITX2c or PANCR in the RNA sequencing with high concordance of effect sizes between the two treatments (r2 = 0.85). Similar to the RNAseq analysis, this miRNAseq analysis shows that the effects of PANCR knockdown on miRNA expression may be largely mediated by through its effect on PITX2c expression. Conclusion: PANCR knockdown decreased PITX2c expression in H9 differentiated cardiomyocytes, and altered the transcriptome similar to PITX2c knockdown. H9 derived cardiomyoctyes were treated with siRNA knockdown (scrambled control, PANCR, PITX2c) in triplicate and RNA and smallRNAs extracted for sequencing.

2015-04-15 | E-GEOD-67844 | biostudies-arrayexpress

Pitx2c regulates axis extension via mesendodermal cell migration

Project description:Pitx2c, a homeodomain transcription factor, is classically known for its left-right patterning role. However, an early wave of pitx2 expression occurs at the onset of gastrulation in several species, indicating a possible earlier role that remains relatively unexplored. Here, we show that in zebrafish, maternal-zygotic (MZ) pitx2c mutants exhibit a shortened body axis indicative of convergence and extension (CE) defects. Live imaging reveals that MZpitx2c mutants display less persistent mesendodermal migration during later stages of gastrulation. Transplant experiments indicate that Pitx2c functions cell non-autonomously to regulate this cell behavior by modulating cell shape and protrusive activity. Using transcriptomic analyses and candidate gene approaches, we identify transcriptional changes in components of the chemokine-ECM-integrin dependent mesendodermal migration network. Together, our results define pathways downstream of Pitx2 that are required during early embryogenesis and reveal novel functions for Pitx2 as a regulator of morphogenesis.

2018-06-22 | GSE114671 | GEO

PANCR, the PITX2 adjacent noncoding RNA, is specifically expressed in human left atria and regulates PITX2c expression

2015-04-15 | GSE67844 | GEO

Genome-wide analysis of adult Pitx2c heterozygous mice

Project description:Analysis of the expression profile of adult mice heterozygous for Pitx2 isoform C. Total RNA obtained from isolated left and right atria from 5 Pitx2c heterozygous mice and 5 wild-type littermates.

2010-06-16 | E-GEOD-22170 | biostudies-arrayexpress

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.

2020-06-19 | GSE152181 | GEO

Decoding the PITX2 controlled genetic network in atrial fibrillation

Project description:Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PV). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2 mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell-type-distinct, PITX2-directed, cis-regulatory grammars controlling target gene expression. The perturbed network targets in each CM were enriched in distinct human AF-predisposition genes, suggesting combinatorial risk for AF-genesis. Our data further reveals that PV and LA Pitx2 mutant CMs signal to endothelial and endocardial cells through BMP10 signaling with pathogenic potential. This work provides a multiomic framework for interrogating the basis of AF-predisposition in the PV of humans.

2022-04-28 | GSE183310 | GEO

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