Single-nuclei transcriptomic analysis of the subthalamic nucleus reveals different Pitx2- positive subpopulations
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE133953 | GEO | 2020/07/03
REPOSITORIES: GEO
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Project description:Single-nuclei transcriptomic analysis of the subthalamic nucleus reveals different Pitx2- positive subpopulations
| PRJNA553206 | ENA
Project description:TRAP translational profiling is a method that allows investigators to genetically characterize specific cell types in complex tissues such as mouse brain. Using this technique we obtained RNA-Seq data from actively translating transcripts present in neurons in the subthalamic nucleus of adult Cbln2-EGFP/Rpl10a (NIDA176) BAC transgenic mice.
2019-12-17 | GSE142147 | GEO
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.
2014-02-01 | GSE47928 | GEO
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
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
Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (five subthalamic nuclei from mice treated with cocaine compared to five subthalamic nuclei from mice treated with saline solution) hybridizations were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments). Each hybridization was numerized hybridization by a GenePix 4000B Microarray Scanner and an Agilent G6525 Microarray Scanner
2015-05-10 | E-GEOD-28523 | biostudies-arrayexpress
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.
2014-02-01 | GSE50399 | GEO
Project description:PITX2 is a homeodomain transcription factor that has a substantial role in cell proliferation and differentiation in various tissues. In this study we have characterized PITX2-regulating genes. These data provide an insightful perspective for further studying PITX2 function and mechanism of action.
2008-12-31 | GSE13216 | GEO
Project description:The Pitx2 gene encodes a homeobox transcription factor that is required for mammalian development. Disruption of PITX2 expression in humans causes congenital heart diseases and is associated with atrial fibrillation (AF), however, the cellular and molecular processes dictated by Pitx2 during cardiac ontogeny remain unclear. To characterize the role of Pitx2 during murine heart development we sequenced over 75,000 single cardiac cell transcriptomes between two key developmental timepoints in control and Pitx2-null embryos. We uncovered that cardiac cell composition was dramatically altered in mutants at both E10.5 and E13.5. Interestingly, the differentiation dynamics of both anterior and posterior second heart field derived progenitor cells were disrupted in Pitx2 mutants. We also uncovered evidence for defects in left-right asymmetry within atrial cardiomyocyte populations. Furthermore, we were able to detail defects in cardiac outflow tract and valve development associated with Pitx2. Our findings offer insight into Pitx2 biology and provide a compilation of gene expression signatures for further detailing the complexities of heart development that will serve as the foundation for future studies of cardiac morphogenesis, congenital heart disease, and arrhythmogenesis.
2019-06-03 | GSE131181 | GEO
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. Pitx2 control and mutant hearts were collected from 3-, 6- and 12-week-old mice. At each time point, three cotrols and three mutants were collected as biological replicates. cDNA microarray analysis was performed using Affymetrix GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA).
2014-02-01 | E-GEOD-50399 | biostudies-arrayexpress