Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132658 | GEO | 2019/08/01
REPOSITORIES: GEO
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Project description:Rationale: The atrioventricular conduction system controls ventricular activation and is delineated by expression of Tbx3. Genome-wide association studies identified genetic variants near TBX3 associated with conduction velocities (PR interval and QRS duration), suggesting minor changes in TBX3 dose affect conduction system function. Objective: To assess whether and how Tbx3 dose reduction affects the integrity of the atrioventricular conduction system. Methods and Results: Electrocardiograms revealed a PR interval shortening and prolonged QT interval and QRS duration in heterozygous Tbx3 mutants compared to wild-types. We observed that the atrioventricular bundle and proximal bundle branches of Tbx3+/- mice after birth became hypoplastic, whereas the size of the atrioventricular node was not affected. The transcriptomes of wild-type and Tbx3+/- atrioventricular nodes were analyzed using BAC-Tbx3-Egfp mice enabling specific isolation of the atrioventricular node by laser capture microdissection followed by RNA-sequencing. Hundreds of genes were slightly but consistently deregulated. Cross-referencing with transcriptome data of isolated cardiomyocytes of the conduction system and chamber myocardium derived from Tbx3+/Venus;BAC-Nppb-Katushka hearts revealed that a set of chamber-enriched genes, including Kcne1 (MinK), Ryr2, and Scn5a, were upregulated in Tbx3+/- atrioventricular nodes, whereas conduction system-enriched genes, including Hcn4 and Cacna2d2, were downregulated. We performed ATAC-sequencing on purified fetal Tbx3+ atrioventricular cardiomyocytes to identify potential atrioventricular-specific regulatory DNA elements on a genome-wide scale, and identified regulatory elements mediating the Tbx3-dependent regulation of Ryr2 and other target genes in the atrioventricular node. Conclusions: Tbx3 dose reduction results in deregulation of a large number of genes affecting the electrical properties of the atrioventricular node and causes failure to maintain the structural integrity of the atrioventricular bundle. These data provide a mechanism underlying differences in PR interval and QRS duration in individuals carrying associated variants in the TBX3 locus.
2019-10-18 | GSE121464 | GEO
Project description:Rationale: The atrioventricular conduction system controls ventricular activation and is delineated by expression of Tbx3. Genome-wide association studies identified genetic variants near TBX3 associated with conduction velocities (PR interval and QRS duration), suggesting minor changes in TBX3 dose affect conduction system function. Objective: To assess whether and how Tbx3 dose reduction affects the integrity of the atrioventricular conduction system. Methods and Results: Electrocardiograms revealed a PR interval shortening and prolonged QT interval and QRS duration in heterozygous Tbx3 mutants compared to wild-types. We observed that the atrioventricular bundle and proximal bundle branches of Tbx3+/- mice after birth became hypoplastic, whereas the size of the atrioventricular node was not affected. The transcriptomes of wild-type and Tbx3+/- atrioventricular nodes were analyzed using BAC-Tbx3-Egfp mice enabling specific isolation of the atrioventricular node by laser capture microdissection followed by RNA-sequencing. Hundreds of genes were slightly but consistently deregulated. Cross-referencing with transcriptome data of isolated cardiomyocytes of the conduction system and chamber myocardium derived from Tbx3+/Venus;BAC-Nppb-Katushka hearts revealed that a set of chamber-enriched genes, including Kcne1 (MinK), Ryr2, and Scn5a, were upregulated in Tbx3+/- atrioventricular nodes, whereas conduction system-enriched genes, including Hcn4 and Cacna2d2, were downregulated. We performed ATAC-sequencing on purified fetal Tbx3+ atrioventricular cardiomyocytes to identify potential atrioventricular-specific regulatory DNA elements on a genome-wide scale, and identified regulatory elements mediating the Tbx3-dependent regulation of Ryr2 and other target genes in the atrioventricular node. Conclusions: Tbx3 dose reduction results in deregulation of a large number of genes affecting the electrical properties of the atrioventricular node and causes failure to maintain the structural integrity of the atrioventricular bundle. These data provide a mechanism underlying differences in PR interval and QRS duration in individuals carrying associated variants in the TBX3 locus.
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Project description:SHM-conduction is a discrete unidirectional model of the human cardiac conduction system. It takes a Boolean input signal from the sinoatrial node (SAN) and includes the refractory behavior of the SAN limiting the maximum signal frequency, the delay between a signal from the SAN and the actual ventricular contraction, and the atrioventricular node generating a signal if no signal has been received for a given period of time.
This project also includes an extension of the model that is able to simulate premature ventricular contractions (PVCs).
2021-03-08 | MODEL2103050002 | BioModels
Project description:The atrioventricular (AV) node is a recurrent source of potentially life-threatening arrhythmias. Nevertheless, limited data are available on its developmental control or molecular phenotype. We used a novel AV node-specific reporter mouse to gain insight into the gene programs determining the formation and phenotype of the AV node. In the transgenic reporter, green fluorescent protein (GFP) expression was driven by 160 kbp of Tbx3 and flanking sequences. GFP was selectively expressed in the AV canal of embryos, and in the AV node of adults, while all other Tbx3+ conduction system components, including the AV bundle, were devoid of GFP expression. Fluorescent AV nodal (Tbx3BAC-Egfp) and complementary working (NppaBAC336-Egfp) myocardial cell populations of E10.5 embryos and E17.5 fetuses were purified using fluorescence-activated cell sorting, and their expression profiles were assessed by microarray analysis. We constructed a comprehensive list of sodium, calcium, and potassium channels specific for the nodal or working myocard. Furthermore, the data revealed that the AV node and the working myocardium phenotypes diverge during development, but that the functional gene classes characteristic for both compartments are maintained. Interestingly, the AV node-specific gene repertoire consisted of multiple neurotrophic factors not yet appreciated to play a role in nodal development. These data present the first genome-wide transcription profiles of the AV node during development, providing valuable information concerning its molecular identity. Keywords: Tbx3, AV node, working myocardium, embryonic development, cardiac development, cardiac conduction system 24 samples: 6x working myocardium stage E10.5 (NppaBAC336-Egfp mice), 6x AV canal myocardium stage E10.5 (Tbx3BAC-Egfp mice), 6x working myocardium stage E17.5 (NppaBAC336-Egfp mice), 6x AV node myocardium stage E17.5 (Tbx3BAC-Egfp mice)
2009-06-02 | E-GEOD-13614 | biostudies-arrayexpress
Project description:Tissue-resident macrophages abound in the distal atrioventricular (AV) node of the heart, electrically couple to conducting cardiomyocytes via Connexin (Cx) 43-containing gap junctions and are implicated in normal and aberrant cardiac conduction.
2017-04-20 | GSE86310 | GEO
Project description:Tissue-resident macrophages abound in the distal atrioventricular (AV) node of the heart, electrically couple to conducting cardiomyocytes via Connexin (Cx) 43-containing gap junctions and are implicated in normal and aberrant cardiac conduction. Moreover, conditional deletion of Cx43 in macrophages (tamoxifen-inducible Cx3cr1 Cx43-/- mice) delays AV conduction and acute depletion of macrophages in Cd11bDTR mice induces progressive AV block.
2017-04-20 | GSE86306 | GEO
Project description:The development of the cardiac conduction system (CCS) is essential for correct heart function. However, critical details on the cell types populating the CCS in the mammalian heart during the development remain to be resolved. Using single-cell RNA sequencing, we generated a large dataset of transcriptomes of ~0.5 million individual cells isolated from murine hearts at six successive developmental corresponding to the early, middle and late stages of heart development. The dataset provides a powerful library for studying the development of the heart's CCS and other cardiac components. Our initial analysis identified distinct cell types between 20 to 26 cell types across different stages, of which ten are involved in forming the CCS. Our dataset allows researchers to reuse the datasets for data mining and a wide range of analyses. Collectively, our data add valuable transcriptomic resources for further study cardiac development, such as gene expression, transcriptional regulation and functional gene activity in developing hearts, particularly the CCS.
2023-04-26 | GSE230531 | GEO
Project description:The atrioventricular (AV) node is a recurrent source of potentially life-threatening arrhythmias. Nevertheless, limited data are available on its developmental control or molecular phenotype. We used a novel AV node-specific reporter mouse to gain insight into the gene programs determining the formation and phenotype of the AV node. In the transgenic reporter, green fluorescent protein (GFP) expression was driven by 160 kbp of Tbx3 and flanking sequences. GFP was selectively expressed in the AV canal of embryos, and in the AV node of adults, while all other Tbx3+ conduction system components, including the AV bundle, were devoid of GFP expression. Fluorescent AV nodal (Tbx3BAC-Egfp) and complementary working (NppaBAC336-Egfp) myocardial cell populations of E10.5 embryos and E17.5 fetuses were purified using fluorescence-activated cell sorting, and their expression profiles were assessed by microarray analysis. We constructed a comprehensive list of sodium, calcium, and potassium channels specific for the nodal or working myocard. Furthermore, the data revealed that the AV node and the working myocardium phenotypes diverge during development, but that the functional gene classes characteristic for both compartments are maintained. Interestingly, the AV node-specific gene repertoire consisted of multiple neurotrophic factors not yet appreciated to play a role in nodal development. These data present the first genome-wide transcription profiles of the AV node during development, providing valuable information concerning its molecular identity. Keywords: Tbx3, AV node, working myocardium, embryonic development, cardiac development, cardiac conduction system
2009-06-02 | GSE13614 | GEO
Project description:The sinoatrial node (SAN) functions as pacemaker of the heart to initiate and drive rhythmic heartbeats. The Hippo signaling pathway is a fundamental pathway for heart development and regeneration. Although abnormalities of Hippo pathway are associated with cardiac arrhythmias in human patients, yet its role in the SAN is unknown. We found that Lats1/2 inactivation caused severe sinoatrial node dysfunction (SND; sick sinus syndrome). Compared to the controls, Lats1/2 CKO mutants exhibited dysregulated calcium handling and increased fibrosis in the sinoatrial node, indicating Lats1/2 function through both cell-autonomous and non-cell-autonomous mechanisms. Notably, the Lats1/2 CKO phenotype was rescued by genetic deletion of Yap and Taz in the CCS, and these rescued mice had normal sinus rhythm and reduced fibrosis of the sinoatrial node, indicating that Lats1/2 function through Yap and Taz. CUT&Tag sequencing data showed that Yap regulates genes critical for calcium homeostasis such as Ryr2 and genes encoding paracrine factors important in intercellular communication and fibrosis induction such as Tgf-β1 and Tgf-β3. Consistently, Lats1/2 CKO mutants had decreased Ryr2 expression and increased Tgf-β1 and Tgf-β3 expression compared with control mice. We reveal for the first time that the canonical Hippo-Yap pathway has a pivotal role in functional homeostasis of the sinoatrial node.
2022-11-29 | GSE202641 | GEO
Project description:Aims: To gain insight into heterogeneity of pacemaker and conduction cells within the sinoatrial node (SAN) and characterize the transcriptome of cardiac endothelial cells (ECs) at single-cell resolution. Methods and results: Single-cell transcriptome analysis of fluorescence activated cell sorting (FACS)-purified SAN cells and surrounding atrial cells from HCN4-GFP knockin mice at postnatal day 2 were performed. Subcluster analysis of SAN cardiomyocyte cluster identified three HCN4+ cell subtypes, including pacemaker cells (PCs), recently identified transitional cells (TCs), and a novel population of His-like conduction cells marked by His-bundle specific marker genes. We additionally refined the molecular signatures of PCs and TCs, and identified Vsnl1, Myl2 and Kcne1 as biomarkers of PCs, TCs and His-like respectively that persistently expressed in the SAN from E15.5 to adult. Furthermore, we observed three endothelial progenitor subtypes (endocardial progenitors, coronary vascular endothelial progenitors, and transitional endothelium migrated from endocardium to coronary vessels) in mouse heart and human fetal heart. These endothelial progenitor subtypes were further identified by mouse lineage tracing analysis. Conclusion: Our study provides a more comprehensive understanding of molecular and cellular signatures underlying pacemaking and conduction of the SAN, and offers new insight into lineage differentiation and diversification of cardiac ECs.
2022-08-18 | GSE182692 | GEO