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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67844 | GEO | 2015/04/15

SECONDARY ACCESSION(S): PRJNA281062

REPOSITORIES: GEO

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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.

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

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

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PANCR, the PITX2 Adjacent Noncoding RNA, Is Expressed in Human Left Atria and Regulates PITX2c Expression.

Project description:Genome-wide studies reveal that genetic variants at chromosome 4q25 constitute the strongest locus associated with atrial fibrillation, the most frequent arrhythmia. However, the mechanisms underlying this association are unknown. Our goal is to find and characterize left atrial-expressed transcripts in the chromosome 4q25 atrial fibrillation risk locus that may play a role in atrial fibrillation pathogenesis.RNA sequencing performed on human left/right pairs identified an intergenic long noncoding RNA adjacent to the PITX2 gene, which we have named PANCR (PITX2 adjacent noncoding RNA). In a human tissue screen, PANCR was expressed specifically in the left atria and eye and in no other chambers of the heart. The levels of PANCR and PITX2c RNAs were highly correlated in 233 human left atrial appendage samples. PANCR levels were not associated with either atrial rhythm status or the genotypes of the chromosome 4q25 atrial fibrillation risk variants. Both PANCR and PITX2c RNAs were induced early during differentiation of human embryonic stem cells into cardiomyocytes. Because long noncoding RNAs often control gene expression, we performed siRNA-mediated knockdown of PANCR, and this treatment repressed PITX2c expression and mimicked the effects of PITX2c knockdown on global mRNA and miRNA expression. Cell fractionation studies demonstrate that PANCR is primarily localized in the cytoplasm.PANCR and PITX2c are coordinately expressed early during cardiomyocyte differentiation from stem cells. PANCR knockdown decreased PITX2c expression in differentiated cardiomyocytes, altering the transcriptome in a manner similar to PITX2c knockdown.

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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.

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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.

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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

Pitx2c regulates axis extension via mesendodermal cell migration

Project description:Pitx2c regulates axis extension via mesendodermal cell migration

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Function of Pitx2 in postnatal heart

Project description:Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Pitx2 haploinsufficient mice are prone to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate within the atrium. Here, we inactivated Pitx2 in postnatal heart and discovered that unstressed adult Pitx2 mutant mice had sinus node dysfunction with impaired atrial conduction, an arrhythmia closely associated with atrial fibrillation. A genome-wide search for Pitx2 transcriptional targets using ChIP-sequencing and RNA expression profiling shows that Pitx2 represses target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators many of which have been implicated in human atrial fibrillation by genome wide association studies. Our findings unveil a Pitx2 postnatal arrhythmogenic function, novel Pitx2 target genes relevant to atrial fibrillation, and reveal that Pitx2 stabilizes the intercalated disc in postnatal atrium. Genomic occupancy profiling of transcriptional factor Pitx2 in postnatal heart.

2014-02-01 | E-GEOD-47928 | biostudies-arrayexpress

Function of Pitx2 in postnatal heart

2014-02-01 | GSE47928 | GEO