Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744017 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15047681_1.fastq.gz | Fastqsanger.gz | |||
| SRR15047681_2.fastq.gz | Fastqsanger.gz | |||
| SRR15047682_1.fastq.gz | Fastqsanger.gz | |||
| SRR15047682_2.fastq.gz | Fastqsanger.gz | |||
| SRR15047683_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE41751: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (expression) GSE41757: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (ChIP-seq) GSE41763: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (Hi-C) Refer to individual Series
2012-10-30 | E-GEOD-41764 | biostudies-arrayexpress
Project description:Background: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by rapid premature aging. Without treatment, accelerated atherosclerosis results in death from heart attack or stroke in the early teens. Recent echocardiographic study has also demonstrated a progressive cardiomyopathy in HGPS patients, characterized by diastolic dysfunction with preserved ejection fraction. We sought to define the cardiovascular phenotype and molecular mechanisms underlying progeria-associated cardiomyopathy in a humanized mouse model, and to determine whether these abnormalities can be corrected by in vivo adenine base editing. Methods: Cardiovascular phenotypes were extensively characterized in LMNAG608G/G608G progeria mice using echocardiography, vascular biomechanical testing, histopathology, transmission electron microscopy, snRNA-seq, RNA in situ hybridization, and plasma biomarker analyses. The effects of in vivo adenine base editing on pathological cardiac remodeling were subsequently evaluated. Results: LMNAG608G/G608G mice developed progressive left ventricular diastolic dysfunction with normal ejection fraction, accompanied by severe central arterial stiffening, impaired vasoreactivity, and reduced vascular distensibility. Histological and ultrastructural analyses of the heart revealed cardiomyocyte nuclear abnormalities, sarcomere disruption, mitochondrial defects, and increased myocardial collagen deposition. Transcriptomic profiling identified a signature of pathological myocardial remodeling, characterized by activation of proteostatic stress responses, suppression of contractile and calcium signaling pathways, enhanced extracellular matrix remodeling and inflammatory signaling, and reactivation of the fetal heart failure gene program. Robust upregulation of Nppa and Nppb, two established heart failure markers, was validated by RNA in situ hybridization and accompanied by significantly elevated circulating NT-proBNP levels. In vivo delivery of an AAV9-encapsulated adenine base editor achieved partial correction of the progeria mutation in the heart and partially reversed cardiomyocyte transcriptional alterations, pathological myocardial remodeling, fibrosis, and heart failure marker expression. Conclusions: A humanized mouse model of HGPS is associated with progressive atherosclerosis, as well as a progressive cardiomyopathy characterized by diastolic dysfunction, pathological myocardial remodeling, and activation of a heart failure transcriptional program. Partial reversal of these abnormalities following in vivo adenine base editing demonstrates that progeria cardiomyopathy is therapeutically modifiable. Future human trials of gene-editing therapies for HGPS should target both the arterial tree and the myocardium.
2026-08-26 | GSE343640 | GEO
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts’ capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and <1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.
2026-06-10 | GSE334271 | GEO
Project description:ABE8e adenine base editor precisely and efficiently corrects a COL7A1 nonsense mutation
| PRJNA872475 | ENA
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare lethal genetic disorder characterized with symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show the RNA sequencing analyses performed on primary mouse fibroblasts of different genotypes (in terms of Progeria; Cas9 background) treated with Cas9 guide RNAs targeting Lmna/Progerin. The mouse genetic background in (1) Pro/Pro;Cas9/+: homozygous for Progeria and heterozygous for transgenic Cas9 The mouse genetic background in (2) Pro/+; +/+: heterozygous for Progeria and no transgenic Cas9 (wild type) The mouse genetic background in (3) +/+;Cas9/+: no Progeria (wild type) and heterozygous for transgenic Cas9
2019-02-15 | GSE122865 | GEO
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. We analyzed gene expression of primary fibroblasts of a Hutchinson-Gilford progeria syndrome patient, a healthy age-matched control, and the patient's healthy father using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array platform. Arrays were filtered and normalized using RMA. Two replicates were performed.
2012-10-30 | E-GEOD-41751 | biostudies-arrayexpress
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal, accelerated-aging disease caused by a mutation in the nuclear envelope protein Lamin A. The resulting mutant protein, progerin, accumulates on the nuclear envelope, causing nuclear blebbing, altered gene expression, and other cellular defects. The primary pathology of HGPS is atherosclerosis, leading to stroke or heart attack. Given that atherosclerosis begins with endothelial dysfunction in non-HGPS individuals, we examined whether the HGPS endothelium has an altered genetic response to shear stress, contributing to atherogenesis. We examined morphology and gene expression of HGPS and healthy iPSC-derived endothelial cells (viECs) after exposure to steady laminar shear stress (12 dynes/cm^2 for 24 hours) in a parallel-plate flow channel. We found that elongation in response to flow is impaired in HGPS viECs compared with healthy viECs. Differential expression (DE) analysis showed fewer significant differentially expressed genes and a lower magnitude of gene expression change after flow in HGPS compared with healthy viECs. Gene Set Enrichment Analysis identified differences in the gene sets altered by flow-induced DE, including Cholesterol Homeostasis, which was overrepresented in HGPS viECs. LGALS3, encoding the atherosclerosis marker galectin-3, was a main driver of this overrepresentation. RT-PCR confirmed LGALS3 as a shear-sensitive gene robustly upregulated in HGPS viECs compared with healthy viECs after flow. Treatment with an adenine base editor correcting the HGPS mutation restored LGALS3 expression to healthy levels. These observations indicate that HGPS ECs have an aberrant molecular response to atheroprotective shear stress, contributing to atherogenesis in HGPS patients.
2026-05-18 | GSE330828 | GEO
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal, accelerated-aging disease caused by a mutation in the nuclear envelope protein Lamin A. The resulting mutant protein, progerin, accumulates on the nuclear envelope, causing nuclear blebbing, altered gene expression, and other cellular defects. The primary pathology of HGPS is atherosclerosis, leading to stroke or heart attack. Given that atherosclerosis begins with endothelial dysfunction in non-HGPS individuals, we examined whether the HGPS endothelium has an altered genetic response to shear stress, contributing to atherogenesis. We examined morphology and gene expression of HGPS and healthy iPSC-derived endothelial cells (viECs) after exposure to steady laminar shear stress (12 dynes/cm^2 for 24 hours) in a parallel-plate flow channel. We found that elongation in response to flow is impaired in HGPS viECs compared with healthy viECs. Differential expression (DE) analysis showed fewer significant differentially expressed genes and a lower magnitude of gene expression change after flow in HGPS compared with healthy viECs. Gene Set Enrichment Analysis identified differences in the gene sets altered by flow-induced DE, including Cholesterol Homeostasis, which was overrepresented in HGPS viECs. LGALS3, encoding the atherosclerosis marker galectin-3, was a main driver of this overrepresentation. RT-PCR confirmed LGALS3 as a shear-sensitive gene robustly upregulated in HGPS viECs compared with healthy viECs after flow. Treatment with an adenine base editor correcting the HGPS mutation restored LGALS3 expression to healthy levels. These observations indicate that HGPS ECs have an aberrant molecular response to atheroprotective shear stress, contributing to atherogenesis in HGPS patients.
2025-12-01 | GSE311520 | GEO
Project description:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.
2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress