Transcriptomic profiling of the postnatal mouse cardiac conduction system
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE231547 | GEO | 2024/06/25
REPOSITORIES: GEO
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Project description:The cardiac conduction system (CCS) consists of distinct components including the sinoatrial node (SAN), atrioventricular node (AVN), His bundle, bundle branches (BB) and Purkinje fibers (PF). Despite an essential role for the CCS in heart development and function, the CCS has remained challenging to interrogate due to inherent obstacles including small cell numbers, large cell type heterogeneity, complex anatomy and difficulty in isolation. We used single-cell RNA-sequencing (scRNA-seq) to perform genome-wide analysis of gene expression of the CCS at single-cell resolution.
2019-08-01 | GSE132658 | 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.
2019-10-18 | GSE121244 | 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.
2019-10-18 | GSE121464 | GEO
Project description:Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. The cardiac conduction system is implicated in arrhythmias, but how it is altered following MI is poorly understood. We demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganised bundling of conduction fibres after MI, global His/Purkinje disruption and regional loss of connexin-40. Single-cell RNA-sequencing revealed that Purkinje cells undergo specific molecular changes to regenerate the network, versus sustained aberrant electrical alterations during fibrotic repair. This manifested functionally as transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modelling the non-regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and ventricular dyssynchrony, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration versus repair and reveal the consequences of MI-induced damage for clinical arrhythmogenesis.
2024-10-31 | GSE245872 | 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
Project description:ETV1 (ER81) was identified as a highly enriched transcription factor in rapidly conducting atrial and His-Purkinje cardiomyocytes. Previous work has shown that ETV1 is a critical factor in determining fast conduction physiology in the heart. This high-throughput sequencing project aims to uncover ETV1-dependent gene networks in cardiomyocytes. These results provide insight into the role of ETV1 in the establishment of rapid conduction zones in the heart.
2018-10-15 | GSE115061 | GEO
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:Purkinje fibers form a network of specializedventricularmyocardial cells to assure a coordinatedpropagation of the electrical impulseduring normalforheartefficientcontractionof the heart.Thedevelopmental origins of Purkinje fibers and their roles during cardiac arrhythmia have been reported.However, theresponse of Purkinje fibers to ischemic injury and theirfunctionrolesduring myocardialregenerationare still illusive. Here we introduceda novel inducibleCreallelemouse linethat specificallylabelsthemousecardiac conduction system. Fate mappingshowed Cre activity in different componentsofindicatedspecific labeling ofthe cardiac conduction system, including the sinoatrial and atrioventricularnodes,as well as the Purkinje fibersdifferentknown and unknowncomponents ofthecardiac conductionsystem. RNA-Seqof laser-captured Purkinje fibers showed a uniqueinjuryresponse occurredafterischemic injuryin thisventricularpart of the conductionsystemand corresponding changes in.Ccellularcompositionchange inofPurkinje fibersafter ischemic injury waswereobserved using immunostaining
2021-07-16 | GSE153182 | GEO
Project description:Cardiac Purkinje cells (PCs) comprise the most distal portion of the ventricular conduction system (VCS) and are essential for synchronous activation of the ventricular myocardium. Contactin-2 (CNTN2), a member of the immunoglobulin superfamily cell adhesion molecules (IgSF-CAMs), was previously identified as a marker of the VCS. Through differential transcriptional profiling we discovered two additional highly enriched IgSF-CAMs in the VCS, NCAM-1 and ALCAM. Immunofluorescence staining showed dynamic expression patterns for each IgSF-CAM during embryonic and early post-natal stages, but ultimately all three proteins became highly enriched in mature PCs. Mice deficient in NCAM-1, but not CNTN2 or ALCAM, exhibited defects in Purkinje cell gene expression and VCS patterning, as well as cardiac conduction disease. Moreover, using ST8sia2 and ST8sia4 knockout mice, we show that inhibition of post-translational modification of NCAM-1 by polysialic acid (PSA) disrupts trafficking of sarcolemmal intercalated disc proteins to Purkinje cell junctional membranes and abnormal expansion of the extracellular space between apposing Purkinje cells. Taken together, our data provide novel insights into the complex developmental biology of the ventricular conduction system.
2021-05-20 | GSE172267 | GEO
Project description:Analysis of gene expression of mESC-derived cardiac purkinje fiber-like cells at mRNA level. Dysfunction of the cardiac conduction system (CCS) significantly impacts pathogenesis of arrhythmia, a major cause of morbidity and mortality. Strategies to derive cardiac conduction cells including Purkinje fiber cells (PC) would facilitate models for mechanistic studies and drug discovery, and also provide new cellular materials for regenerative therapies. A high-throughput chemical screen using CCS:lacZ and Contactin2:eGFP (Cntn2:eGFP) reporter embryonic stem cell (ESC) lines was used to discover a small molecule, sodium nitroprusside (SN), that efficiently promotes the generation of cardiac cells that express gene profiles and generate action potentials of PC-like cells. Imaging and mechanistic studies suggest that SN promotes the generation of PC from cardiac progenitors initially expressing cardiac myosin heavy chain, and that it does so by activating cAMP signaling. These findings provide a novel strategy to derive scalable PC, along with insight into the ontogeny of CCS development.
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