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Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.

ABSTRACT: Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.

PROVIDER: PRJNA1195932 | ENA |

REPOSITORIES: ENA

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

Project description:Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer [scRNA-Seq]

| PRJNA1189809 | ENA

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

Project description:Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer [RNA-seq]

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

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

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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

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

2024-11-27 | GSE282693 | GEO

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

2024-11-27 | GSE282670 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [1]

Project description:Circadian rhythms have been implicated in regulating skeletal muscle structure and function, but no mechanisms have connected the molecular clock to sarcomeric proteins. We identified an isoform shift in the sarcomeric ruler, titin, and showed that the skeletal muscle molecular clock regulates titin isoform and subsequently sarcomere length through RBM20, an RNA binding protein that controls titin splicing.

2022-09-07 | GSE172067 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [2]

2022-09-07 | GSE189863 | GEO

Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.

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

2024-12-10 | GSE283867 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing

Project description:The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing

| PRJNA784914 | ENA