Genome-wide occupancy profile of Tbx3 in adult mouse whole heart
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Vincent Christoffels
PROVIDER: E-GEOD-44821 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The molecular mechanisms governing heart development provide an important framework to understand congenital heart disease. The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. To better understand the molecular mechanism underlying atrioventricular canal versus chamber myocardium expression, a double-reporter transgenic mouse line was generated in which the expression of EGFP (green fluorescent protein) and Katushka (red fluorescent protein) are selectively expressed in the atrioventricular canal and in the chamber myocardium, respectively. We assessed the genome-wide H3K27ac pattern in isolated embryonic AV canal and in chamber cardiomyocytes, respectively. EGFP and Katushka-positive cells were purified by FACS and fixed. ChIP was performed with the truemicro ChIP (Diagenode) according to the manufacturer’s protocol using the H3K27ac antibody (abcam ab4729). Chipped DNA were subjected to library preparation using the 5500 Series SOLiD™ Systems ample preparation kit (Applied Biosystems) according to manufactures recommendations and sequenced using the 5500 wildfire system (SOLiD).
2014-03-06 | E-GEOD-55611 | biostudies-arrayexpress
Project description:The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Examination of 3 cardiac transcription factors and p300 in adult mouse heart
2012-06-22 | E-GEOD-35151 | biostudies-arrayexpress
Project description:The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3 in the mouse heart, uncovering cardiac enhancers throughout the genome.
2013-03-05 | GSE44821 | GEO
Project description:The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome.
2012-06-22 | GSE35151 | GEO
Project description:T-box transcription factors play critical roles in the development and identity of the heart. Tbx5 has been implicated as a regulator of the fast-conducting, ventricular conduction system, while Tbx3 has been implicated as a regulator of the slow-conducting node. We hypothesize TBX5 and TBX3 share common binding sites in cardiomyocytes to positively or negatively regulate transcription, respectively, for cardiac cell identity and conduction. To this end, we performed ChIP-sequencing to identify localization of TBX5 during fetal heart development and have compared it with previously published histone (GEO Series: GSE31039; ENCODE Accessions: ENCSR080GQM, ENCSR000CDL, ENCSR000CDM, ENCSR052CDF, ENCSR345RKE, ENCSR007XTC, ENCSR360ANE, ENCSR000CDK, and ENCSR357OED) and TBX3 ChIP-seq (GSM862695).
2020-04-21 | GSE139803 | GEO
Project description:to study the effect of induced expression of TBX3 within the atrium of the heart Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies. 5 TBX3 expressing left atrial appendage samples (Tamoxifen-treated Myh6MCM;CTBX3 adult male mice) and 6 controls ((Tamoxifen-treated Myh6MCM adult male mice)
2011-09-30 | E-GEOD-31969 | biostudies-arrayexpress
Project description:to study the effect of induced expression of TBX3 within the atrium of the heart Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies.
2011-10-01 | GSE31969 | GEO
Project description:In this study, we aimed to differentiate atrioventricular (AV) canal-like cardiomyocytes (AVCM) from hiPSCs to facilitate the study of disorders that affect the AV conduction axis. hiPSC-derived AVCM preferentially expressed AV canal-associated genes MSX2, TBX2 and TBX3. Single cell RNA sequencing and comparative analysis with mouse heart further validated their AV canal-like identity. In addition, hiPSC-AVCM demonstrated sensitivity to ivabradine and carbachol, indicating the presence of key nodal currents If and IKACh. To model the AV conduction axis, we created an organoid-based tissue model. These so-called “assembloids” consisted of atrial, AVC, and ventricular organoids, which exhibited spontaneous contractions and unidirectional conduction with impulses initiated predominantly at the atrial end. Remarkably, we observed slower conduction in the AVC region of the assembloid, effectively recapitulating the “fast-slow-fast” conduction pattern found in the early heart tube. Our results demonstrate that hiPSC-derived AVCM recapitulate molecular and electrophysiological properties of in vivo AV canal cardiomyocytes and tissue models incorporating this cell type enhance our ability to evaluate complex cardiac conduction disorders.
2024-09-10 | GSE250173 | 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