Ontology highlight
ABSTRACT:
PROVIDER: PRJNA495150 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7984012.fastq.gz | Fastqsanger.gz | |||
| SRR7984013.fastq.gz | Fastqsanger.gz | |||
| SRR7984014.fastq.gz | Fastqsanger.gz | |||
| SRR7984015.fastq.gz | Fastqsanger.gz |
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Project description:Abnormalities of ventricular action potential (AP) cause malignant cardiac arrhythmias and sudden cardiac death. Here, we sought to identify microRNAs (miRNAs) that regulate the human cardiac AP and asked whether their manipulation allows for therapeutic modulation of AP abnormalities. Quantitative analysis of the miRNA targetomes in human cardiac myocytes identified miR-365 as a primary miRNA to regulate repolarizing ion channels. AP recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs) showed that elevation of miR-365 level significantly prolonged AP duration in hiPSC-CMs derived from a Short-QT syndrome (SQTS) patient, whereas specific inhibition of miR-365 normalized pathologically prolonged AP in Long-QT syndrome (LQTS) iPSC-CMs. Transcriptome analyses in human iPSC-CMs at bulk and single-cell level corroborated the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional AP-regulating genes by this miRNA. Whole-cell patch clamp experiments revealed miR-365-based regulation of repolarizing ionic currents. Finally, refractory period measurements in human myocardial slices substantiated the prolonging effect of miR-365 on AP duration also in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac AP duration by targeting key factors of cardiac repolarization.
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Project description:Abnormalities of ventricular action potential (AP) cause malignant cardiac arrhythmias and sudden cardiac death. Here, we sought to identify microRNAs (miRNAs) that regulate the human cardiac AP and asked whether their manipulation allows for therapeutic modulation of AP abnormalities. Quantitative analysis of the miRNA targetomes in human cardiac myocytes identified miR-365 as a primary miRNA to regulate repolarizing ion channels. AP recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs) showed that elevation of miR-365 level significantly prolonged AP duration in hiPSC-CMs derived from a Short-QT syndrome (SQTS) patient, whereas specific inhibition of miR-365 normalized pathologically prolonged AP in Long-QT syndrome (LQTS) iPSC-CMs. Transcriptome analyses in human iPSC-CMs at bulk and single-cell level corroborated the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional AP-regulating genes by this miRNA. Whole-cell patch clamp experiments revealed miR-365-based regulation of repolarizing ionic currents. Finally, refractory period measurements in human myocardial slices substantiated the prolonging effect of miR-365 on AP duration also in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac AP duration by targeting key factors of cardiac repolarization.
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Project description:Abnormalities of ventricular action potential (AP) cause malignant cardiac arrhythmias and sudden cardiac death. Here, we sought to identify microRNAs (miRNAs) that regulate the human cardiac AP and asked whether their manipulation allows for therapeutic modulation of AP abnormalities. Quantitative analysis of the miRNA targetomes in human cardiac myocytes identified miR-365 as a primary miRNA to regulate repolarizing ion channels. AP recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs) showed that elevation of miR-365 level significantly prolonged AP duration in hiPSC-CMs derived from a Short-QT syndrome (SQTS) patient, whereas specific inhibition of miR-365 normalized pathologically prolonged AP in Long-QT syndrome (LQTS) iPSC-CMs. Transcriptome analyses in human iPSC-CMs at bulk and single-cell level corroborated the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional AP-regulating genes by this miRNA. Whole-cell patch clamp experiments revealed miR-365-based regulation of repolarizing ionic currents. Finally, refractory period measurements in human myocardial slices substantiated the prolonging effect of miR-365 on AP duration also in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac AP duration by targeting key factors of cardiac repolarization.
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Project description:Modeling Atrial Fibrillation (AF) in a Dish using Atrial iPSC-Derived Cardiomyocytes (iPSC-CMs)
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Project description:Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) or directly reprogrammed from non-myocytes (induced cardiomyocytes, iCMs) are promising sources for heart regeneration or disease modeling. However, the similarities and differences between iPSC-CM and iCM are still unknown. Here we performed transcriptome analyses of beating iPSC-CMs and iCMs generated from cardiac fibroblasts (CFs) of the same origin. Although both iPSC-CMs and iCMs establish CM-like molecular features globally, iPSC-CMs exhibit a relatively hyperdynamic epigenetic status while iCMs exhibit maturation status that more resemble adult CMs. Based on gene expression of metabolic enzymes, iPSC-CMs primarily employ glycolysis while iCMs utilize fatty acid oxidation as the main pathway. Importantly, iPSC-CMs and iCMs exhibit different cell cycle status, alteration of which influenced their maturation. Therefore, our study provides a foundation for understanding the pros and cons of different reprogramming approaches.
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