Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA394989 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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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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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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:The cardiac conduction system (CCS) comprises a network of highly specialized cells, including sinoatrial node, atrioventricular node, His bundle, bundle branches and Purkinje fibers. To uncover the transcriptomic landscape across the postnatal CCS and comparative profiling of different CCS components, we conducted scRNA-seq in purified postnatal CCS cells and spatial transcriptomic analysis in the postnatal CCS reporter mouse heart.
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Project description:Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of disease-related deaths, yet, the underlying mechanisms remain unclear. Herein, we report that upregulation of a non-muscle splice isoform of RNA binding protein RBFOX2 in DM1 heart tissue—due to altered splicing factor and microRNA activities—induces the characteristic cardiac conduction defects detected in DM1 individuals. Mice engineered to express the non-muscle RBFOX2 isoform in heart via tetracycline- inducible transgenesis, or CRISPR/Cas9 targeted genome editing, reproduced DM1- related cardiac-conduction delay and spontaneous episodes of arrhythmia. Furthermore, by integrating RNA binding with cardiac transcriptome datasets of DM1 patients, and mice expressing the non-muscle RBFOX2 isoform, we identified a core network of RBFOX2-driven splicing defects in sodium, potassium, and calcium channels that can alter their rate of ion diffusion and electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis.
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