Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA577917 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10294113_1.fastq.gz | Fastqsanger.gz | |||
| SRR10294113_2.fastq.gz | Fastqsanger.gz | |||
| SRR10294114_1.fastq.gz | Fastqsanger.gz | |||
| SRR10294114_2.fastq.gz | Fastqsanger.gz |
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Project description:Vascular dysfunction is one of the typical characteristics of aging, but its contributing roles to systemic aging and the therapeutic potential is lacking experimental evidence. Accumulating data suggest that the mechanisms underlying aging are similar to those governing Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disease, in which affected patients succumb to cardiovascular diseases (CVDs). Here, we generated a knock-in mouse model with the causative HGPS LmnaG609G mutation, called progerin. We crossed Lmnaf/f mice with a Tie2-Cre line to get Lmnaf/f;TC mice, which exhibit defective microvasculature and neovascularization, accelerated aging and shortened lifespan. Single-cell transcriptomic analysis of murine lung endothelial cells (MLECs) revealed a significant upregulation of inflammatory response. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.
2019-10-17 | GSE138975 | GEO
Project description:Primary skin fibroblasts from a HGPS patient and an age-matched control wild-type individual were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). Knock-down of BRD4 in this TRS-HGPS cell line (TRS-HGPS-shBRD4) was achieved by retroviral introduction of independent shRNAs (shBRD4-1 to -3) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis.
2014-10-02 | GSE60519 | GEO
Project description:Primary skin fibroblasts from a HGPS patient and an age-matched control wild-type individual were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). Knock-down of BRD4 in this TRS-HGPS cell line (TRS-HGPS-shBRD4) was achieved by retroviral introduction of independent shRNAs (shBRD4-1 to -3) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. 2 biological replicates are included for TRS-WT and TRS-HGPS cell lines. 3 biological replicates are included for TRS-HGPS-shBRD4 (derived from 3 independent shRNAs against BRD4)
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Project description:HGPS is a rare premature ageing disease, caused by a mutation in the LMNA gene, which activates a cryptic splice site, resulting in the production of a mutant lamin A isoform, called progerin. Sporadic usage of the same cryptic splice site has been observed with normal physiological aging. As it is unknown how HGPS causes premature ageing defects, we set out to determine the gene signature of both young healthy individuals, old healthy individuals, as well as HGPS patients.
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Project description:Premature aging disorders provide a lens through which to study the drivers of aging. In Hutchinson-Gilford progeria syndrome (HGPS) a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We used stable isotope labeling and quantitative mass spectrometry to investigate nuclear protein homeostasis in primary HGPS-derived cells.
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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). The molecular basis underlying premature aging driven cardiovascular diseases remains incompletely understood. Since endothelial dysfunction is involved in the initiation and progression of cardiovascular diseases. We hypothesized that HGPS-causing progerin (a mutant form of lamin A) and farnesylated prelamin A drives endothelial dysfunction and cardiovascular disease. In our study, we performed transcriptomic profiling of ZMPSTE24-/- mouse endothelial cells, hoping to find the missing link between progeria and atherosclerosis. We observed that ZMPSTE24-/- endothelial cells have increased farnesylated prelamin A accumulation, and show nuclear structure abnormality. Analysis of RNA-seq data revealed that multiple endothelial homeostasis-related genes and pathways are altered by ZMPSTE24 deletion. Further studies are needed to characterize the biological functions of ZMPSTE24 in the pathogenesis of progeria-associated atherosclerosis.
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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for physiological aging. The cellular machinery mediating age-associated hallmarks in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS treatment. In this study, we showed that deficiencies in mitophagy impaired mitochondrial quality and contributed to cellular phenotypes associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-related phenotypes of HGPS-MSCs by inhibiting the cGAS-STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotype (SASP). Furthermore, by utilizing UMI-77, an effective inducer of mitophagy, we showed that mitophagy induction can alleviate aging-associated phenotypes in both HGPS mice and naturally aged mice. In summary, our results uncover that mitophagy defects mediate mitochondrial dysfunction and aging-associated phenotypes in HGPS models, highlight the function of mitochondrial homeostasis in HGPS progression, and suggest that mitophagy could be exploited as a promising therapeutic target for both HGPS and aging.
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Project description:We analyzed and compared global gene expression changes in fibroblasts from human subjects with HGPS compared to age matched controls. We then treated both control and HGPS fibroblasts with a protein farnesyltransferase inhibitor (FTI), a medication currently used in clinical trials to treat HGPS, to look for a reversal of the gene defects present in HGPS fibroblasts.
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