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Loss of Pitx2c predisposes to arrhythmia and atrial fibrillation pathologies via structural and metabolic dysfunction

ABSTRACT: Loss of Pitx2c predisposes to arrhythmia and atrial fibrillation pathologies via structural and metabolic dysfunction

PROVIDER: PRJNA527965 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8749823.fastq.gz	Fastqsanger.gz
	SRR8749824.fastq.gz	Fastqsanger.gz
	SRR8749825.fastq.gz	Fastqsanger.gz
	SRR8749826.fastq.gz	Fastqsanger.gz
	SRR8749827.fastq.gz	Fastqsanger.gz

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Loss of Pitx2c predisposes to arrhythmia and atrial fibrillation pathologies via structural and metabolic dysfunction

Project description:RNAseq profiling of embryonic zebrafish hearts was performed to identify differentially expressed genes downstream of Pitx2c.

2019-10-25 | GSE128511 | GEO

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

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

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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.

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

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

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

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

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

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Single-cell profile of atrial human fibroblasts in cardiac arrhythmia atrial fibrillation (AF) - 10x

Project description:Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major contributor to population mortality and morbidity. The goal of this study is to explore molecular mechanisms of the AF-induced profibrotic remodelling in human atrial fibroblasts (ACFs). Specifically, we assessed single-cell transcriptome of cultured human ACFs treated with calcitonin(CT) or vehicle (from 6 individual patients) and of freshly-isolated ACFs from patients with AF (4 individual patients) vs controls (4 individual patients). We found that ACF transcriptome was unaltered by CT in cultured ACFs, and identified 5 transcriptional clusters with 23 differentially expressed transcripts in AF in freshly-ioslated ACFs.

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