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Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling

ABSTRACT: Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling

PROVIDER: PRJNA394989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5839510.fastq.gz	Fastqsanger.gz
	SRR5839511.fastq.gz	Fastqsanger.gz
	SRR5839512.fastq.gz	Fastqsanger.gz
	SRR5839513.fastq.gz	Fastqsanger.gz
	SRR5839514.fastq.gz	Fastqsanger.gz

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Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling

Project description:Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling

| PRJNA394989 | ENA

Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling [ChIP-seq]

Project description:Sudden cardiac death is the number one cause of death worldwide. Major causes of sudden cardiac death include myocardial infarction and cardiomyopathies. To develop novel therapeutic strategies, we need to identify key factors that are required for proper cardiac function and are dysregulated in the diseased heart. Under this notion, we found T-box 5 (TBX5), a transcription factor regarded solely in the context of congenital heart disease, to be downregulated in human diseased left ventricles. To investigate the effects of TBX5 loss in the adult heart, we generated an inducible ventricular cardiomyocyte specific knock-out mouse model (vTbx5KO). We performed integrative genome-wide chromatin occupancy and transcriptomic analysis and identified 47 downregulated transcripts in vTbx5KO that contain TBX5 active enhancers. The TBX5 targets in the ventricle included genes implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5) as well as cardiac protection upon stress (Fhl2, Gpr22, Fgf16). In line with this analysis, vTbx5KO mice presented cardiac conduction defects and arrhythmias at baseline as well as exacerbated cardiac remodeling upon Angiotensin II-induced hypertrophy. In conclusion, this study uncovers a novel protective role of TBX5 upon cardiac remodeling and renders TBX5 as an interesting therapeutic target.

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Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling [RNA-seq]

2020-07-19 | GSE101613 | GEO

Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-19 | GSE101615 | GEO

Expression profiling of the E10.5 cardiac conduction system using MinKGFP BAC transgenic mice

Project description:Proper development of the specialized cardiac conduction system is crucial for function of the mature heart. Tools for isolation and in-vivo study of the conduction system are limited. The goal of this study was to identify pathways important for conduction system development. We generated a BAC transgenic mouse line, minKGFP, that marks the conduction system during embryogenesis and in adulthood. GFP is expressed in this line at high levels in conduction system myocardium (minkGFP high) and low levels in chamber myocardium (minKGFP low). We used this mouse line to isolate E10.5 conduction system cells, and performed transcriptional profiling on these cells to identify pathways with potential roles in specification of the developing cardiac conduction system.

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Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction

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.

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Neural Cell Adhesion Molecule (NCAM-1) is Required for Ventricular Conduction System Development

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.

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Project description:Transcriptomic profiling of the postnatal mouse cardiac conduction system

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