Pitx2c regulates axis extension via mesendodermal cell migration
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ABSTRACT:
PROVIDER: PRJNA472092 | ENA |
REPOSITORIES: ENA
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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.
2018-06-22 | GSE114671 | GEO
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 late stages of gastrulation. Transplant data 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 Pitx2c that are required during early embryogenesis and reveal novel functions for Pitx2c as a regulator of morphogenesis.
| S-EPMC6023614 | biostudies-literature
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
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 | GSE138528 | GEO
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
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
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.
2015-04-15 | GSE67844 | GEO
Project description:The epigenome of a cell is established and maintained by chromatin modifiers and remodelers, which are recruited to the chromatin by specific transcription factors. In this report, we show that nodal cross-talks with the epigenome through TRIM33-H3K18ac to mediate mesendodermal genes expression. The chromatin accessibility at mesendodermal genes depends on TRIM33. Moreover, histone acetylation is essential for TRIM33 recruitment to many nodal target genes involved in mesendodermal differentiation. The distribution pattern of the H3K18ac mark changes from foci to expanded domains at the mesendodermal genes promoter during embryonic stem cells (ESCs) differentiation to embryoid bodies (EBs). This could be the cue to facilitate TRIM33 colocalized with Smad2/3 at chromatin in EBs but not in ESCs. TRIM33 interacts with the H3K18ac “writer” p300 dependent on nodal signaling, providing a positive feedback to promote activation of mesendodermal genes and association with HDAC1 plays a negative role in activation of mesendodermal genes.
2019-06-01 | GSE115169 | GEO
Project description:RNAseq profiling of embryonic zebrafish hearts was performed to identify differentially expressed genes downstream of Pitx2c.
2019-10-25 | GSE128511 | GEO
Project description:Human induced pluripotent stem cells (iPS cells) resemble embryonic stem cells and can differentiate into cell derivatives of all three germ layers. However, frequently the differentiation efficiency of iPS cells into some lineages is rather poor. Here, we found that fusion of iPS cells with human hematopoietic stem cells (HSC) enhances iPS cell differentiation. Such iPS hybrids showed a prominent differentiation bias towards hematopoietic lineages but also towards other mesendodermal lineages. Additionally, during differentiation of iPS hybrids expression of early mesendodermal markers - Brachyury (T), MIX1 Homeobox-Like Protein 1 (MIXL1) and Goosecoid (GSC) - appeared with faster kinetics than in parental iPS cells. Following iPS hybrid differentiation there was a prominent induction of NODAL and inhibition of NODAL signaling blunted mesendodermal differentiation. This indicates that NODAL signaling is critically involved in mesendodermal bias of iPS hybrid differentiation. In summary, we demonstrate that iPS cell fusion with HSC prominently enhances iPS differentiation. 11 samples were hybridized GeneChip Human Gene 1.0 ST Arrays (Affymetrix)
2014-08-06 | E-GEOD-58457 | biostudies-arrayexpress