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

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

ORGANISM(S): Danio rerio

PROVIDER: GSE128511 | GEO | 2019/10/25

REPOSITORIES: GEO

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

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

| PRJNA527965 | ENA

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 [ChIP-seq]

2019-10-08 | GSE138528 | 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

| PRJNA671280 | ENA

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

Single-cell profile of atrial human fibroblasts in cardiac arrhythmia atrial fibrillation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-10 | GSE148507 | GEO

PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation.

Project description:ObjectiveThis study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation.MethodsA cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual-luciferase reporter assay system.ResultsTwo novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts.ConclusionThe findings of this study associate PITX2c loss-of-function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia.

| S-EPMC3870307 | biostudies-literature

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

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