SnRNAseq for Modeling long QT syndrome using gene-edited pigs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1322450 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Modeling long QT syndrome using gene-edited pigs
| PRJNA1216026 | ENA
Project description:To date, KCNH2 mutations identified in patients with long QT syndrome type 2 (LQT2) have been extensively studied using heterologous expression systems. While these systems allow for the evaluation of the pathogenicity of specific hERG mutations through the overexpression of mutant channels, they fail to recapitulate the full spectrum of electrophysiological alterations and ion channel remodeling that occur in cardiomyocytes under physiological conditions in LQT. Existing zebrafish and rodent models are also limited in their ability to faithfully model human QT interval abnormalities due to substantial differences in lifespan, size, anatomy, and physiology. For instance, rodents exhibit a much higher heart rate and significantly shorter action potential duration (APD) than humans. Moreover, IKr is the major repolarizing current in human ventricles, whereas its inhibition in rodents has minimal impact on ventricular repolarization, rendering genetic mouse models inadequate for the study of LQT2. Thus, there is a critical need to develop animal models that can more accurately mimic human inherited arrhythmias. To address this gap, we generated a miniature pig model of LQT2, capitalizing on the physiological similarities to humans, as well as advantages in breeding and genome editing compared to non-human primates. To investigate the mechanisms by which KCNH2 mutations lead to LQT, we performed single-nucleus RNA sequencing to compare the transcriptomes of ventricular tissues from KCNH2-mutant pigs and wild-type controls.
2025-09-11 | GSE307648 | GEO
Project description:To date, KCNH2 mutations identified in LQT2 patients have been heavily studied by heterologous expression systems, allowing for pathogenicity evaluation of a certain hERG mutation by overexpressing mutant channels. However, they fall short in mimicking the full spectrum of electrophysiological changes and ion channel remodeling that occur in cardiomyocytes under physiological conditions in the context of LQT. Due to the marked differences in the lifespan, size, anatomy and physiology from humans, current zebrafish and rodent models cannot fully mimic the abnormal QT interval diseases 2. For instance, rodents exhibit an extremely higher heart rate and a much shorter action potential duration (APD) compared to humans. IKr is the predominant repolarizing current in human ventricles while inhibition of IKr in rodents has no significant effect on ventricular repolarization, making it infeasible to study LQT2 by genetic mouse model 3. Hence, there is a crucial need to construct an animal model capable of mimicking human inherited arrhythmia conditions. To address the above scientific question, we chose to create a miniature pig model. Given many physiological similarities with humans, and breeding and genome editing advantages (when compared to non-human primates), To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls
2025-02-03 | GSE288082 | GEO
Project description:Induced pluripotent stem cell modeling of patients and drugs at risk for QT prolongation
| PRJNA671350 | ENA
Project description:Our goal is to identify high-confidence candidate genes associated with sub-threshold QT interval loci. We predicted enhancer-promoter targets using two different methods.
2014-10-10 | GSE53567 | GEO
Project description:Right atrial snRNAseq analysis
| PRJNA1236287 | ENA
Project description:Peribacillus frigoritolerans QT-140 TE12474 genome sequencing
| PRJNA1115250 | ENA
Project description:Our goal is to identify high-confidence candidate genes associated with sub-threshold QT interval loci. We predicted enhancer-promoter targets using two different methods. 1) We used the correlation in activity between enhancers and transcribed genes across 59 human cell lines and tissues to identify significantly correlated enhancer-promoter pairs that represent potential regulatory interactions. 2) We used chromosome conformation capture followed by high-throughput sequencing (4C-seq) to probe physical enhancer-promoter interactions.
2014-10-10 | E-GEOD-53567 | biostudies-arrayexpress
Project description:Preclinical models are essential for advancing therapeutic strategies in hepatocellular carcinoma (HCC), an aggressive disease with poor survival outcomes. Here, we established genetically defined HCC models by ex vivo CRISPR editing of porcine hepatocytes. Hepatocytes were isolated from Yucatan minipigs and subjected to combinations of 2-4 gene alterations, including CRISPR-mediated knockout of tumor suppressor genes (TP53, PTEN, CDKN2A, AXIN1), with or without c-myc overexpression. Edited hepatocytes were expanded in culture, and those harboring at least three gene alterations formed tumors in SCID mice that recapitulated human HCC histologically. Clonal derivatives from the cell pools generated mouse xenograft tumors with distinct liver cancer histological features. Transcriptomic profiling of the cell models and xenograft tumors revealed activation of cell cycle pathways and similarity with human HCC. Further, autologous intrahepatic implantation of edited hepatocytes into pigs produced tumors with prominent immune infiltration, establishing an immune-competent large-animal model of HCC. Collectively, this HCC modeling platform provides insights into cooperative gene alterations underlying HCC pathogenesis and enables preclinical testing of systemic and locoregional therapies in a clinically relevant large-animal context.
2025-12-01 | GSE311743 | GEO
Project description:snRNAseq of human limbus tissue
| PRJNA935339 | ENA