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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

ABSTRACT: Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

PROVIDER: PRJNA759628 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15691300_1.fastq.gz	Fastqsanger.gz
	SRR15691300_2.fastq.gz	Fastqsanger.gz
	SRR15691301_1.fastq.gz	Fastqsanger.gz
	SRR15691301_2.fastq.gz	Fastqsanger.gz
	SRR15691302_1.fastq.gz	Fastqsanger.gz

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

Project description:Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

| PRJNA759626 | ENA

Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

Project description:Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

| PRJNA759629 | ENA

Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

Project description:Titintruncating variants(TTNtv) have been identified as the single largestgenetic cause of dilated cardiomyopathy(DCM). In this studywe modeled the disease phenotypes of TTNtv-induced DCM in hiPSC-CMsusing CRISPR/Cas9 genome editing and tissue engineering technologies. Transcriptomic, cellular and micro-tissue studies revealed that TTNtv hiPSC-CMs displayed pathogenic proteinopathy, sarcomere defects, aberrant Na+channel activities and, most importantly, contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. On the other hand, TTNtv cellular defects did not interfere with normal function of the core contractile machinery, actin-myosin-troponin-Ca2+complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomicchanges that promotereversalof DCM disease signatures, as revealed by single-cell RNA-seqanalysis.Taken together, our findings depict the underlying pathogenic mechanisms of TTNtv-induced DCMand demonstrate the validity of sarcomere modulators as potentialtherapeutic agentsfor this disease.

2023-01-25 | GSE183217 | GEO

Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

2023-01-25 | GSE183216 | GEO

Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery.

Project description:Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na+ channel activities, and contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. However, TTNtv cellular defects did not interfere with the function of the core contractile machinery, the actin-myosin-troponin-Ca2+ complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomic changes that promote reversal of DCM disease signatures. Together, our findings elucidate the underlying pathogenic mechanisms of A-band TTNtv-induced DCM and demonstrate the validity of sarcomere modulators as potential therapeutics.

| S-EPMC9860080 | biostudies-literature

Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

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

2023-01-25 | GSE183218 | GEO

Contractile work contributes to maturation of energy metabolism in hiPSC-derived cardiomyocytes

Project description:Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for biomedical application, but they are immature and have not undergone metabolic shift related to early postnatal development. Cultivation of hiPSC-CM in 3D engineered heart tissue (EHT) format leads to morphological maturation. This study compared the mitochondrial and metabolic state of hiPSC-CM in standard 2D culture and the EHT format and determined the influence of contractile activity. HiPSC-CM in EHTs showed ~2-fold higher number of mitochondria (electron microscopy), mitochondrial mass (mitotracker), DNA (Mt-ND1, Mt-ND2), and protein abundance (proteome) than in 2D culture. While hiPSC-CM exhibited the principal ability to use glucose, lactate and fatty acids as energy substrates irrespective of culture format, hiPSC-CM in 3D performed more oxidation of glucose, lactate and fatty acid, and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological inhibition of contractile force, suggesting that contractile work participates in mitochondrial development hiPSC-CM. In conclusion, contractile work in the EHT format contributes to metabolic maturation of hiPSC-CM.

2018-03-06 | PXD008205 | Pride

RNA sequencing of wildtype and homozygous titin A178D mouse left ventricle samples

Project description:Truncating variants in titin can cause dilated cardiomyopathy, however, the role of missense titin variants is less clear. In humans the heterozygous titin A178D variant is associated with dilated cardiomyopathy with left ventricular non-compaction. Using CRISPR-Cas9 mediated homology-directed repair the A178D titin variant was introduced into a mouse model. Homozygous A178D mice showed features of dilated cardiomyopathy. Total RNA was extracted from the left ventricles of WT and homozygous A178D littermate control mice and RNA-sequencing performed. Different patterns of gene expression were identified in wildtype and homozygous A178D left ventricles.

2021-02-26 | GSE154504 | GEO

Titin splicing

Project description:Titin is a striated muscle-specific giant elastic protein and largely responsible for the generation of the diastolic force in the cardiac myocyte. Cardiac titin undergoes developmental changes in isoform expression during the course of cardiac development. At present, at least five size classes of titin isoforms (N2B and N2BA-A1, A2, N1, N2) have been identified using SDS agarose gel electrophoresis. The larger titin isoform N2BAs gradually decreased with ages, in contrast, the smaller titin isoform N2B increased in normal cardiomyocyte, and cardiac myocytes containing a higher proportion of the smaller titin isoform N2B have stronger passive tension than that with a lower proportion of the larger titin isoform N2BAs. Recently we found an autosomal dominant mutation which caused totally opposite cardiac titin isoform expression as compared to developmental stages. The larger total titin isoform N2BA increased in mutant rat cardiac myocytes with ages instead of the smaller cardiac titin isoform N2B. For the moment, mechanism of titin isoform switch is still unknown, therefore, the mutant rats will give us nevol sight to elucidate the titin splicing mechanism. Keywords: Titin isoforms, autosomal dominant mutation

2008-06-10 | GSE11137 | GEO

Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer [ATAC-seq]

Project description:Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality, while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive the expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together, these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.

2024-12-14 | GSE283866 | GEO

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