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Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional profiling of human cancer cell lines upon ZMPSTE24 silencing

ABSTRACT: Defining the aging-cancer relationship is a challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate many features of aging. However, their short lifespan and cell-intrinsic and -extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. To circumvent these limitations we have generated Zmpste24 mosaic mice. Interestingly, these mice develop normally - revealing cell-extrinsic mechanisms are preeminent in progeria- and display decreased incidence of infiltrating oral carcinomas. Moreover, ZMPSTE24 knock-down reduces human cancer cell invasiveness. Our results disclose the ZMPSTE24-prelamin A system as an example of antagonistic pleiotropy on cancer and aging, support the potential of cell-based and systemic therapies for progeria, and highlight ZMPSTE24 as a new anticancer target. We used siRNAs to silence ZMPSTE24 in different human cancer cell lines (SCC-40, SCC-2, A549 and MDA-MB-231), and compared their RNA expression profiles with those of mock treated cells. Each experimental condition (ZMPSTE24 or Scrambled siRNA) was performed in duplicate. Thus, a total of 16 array hybridizations were performed.

ORGANISM(S): Homo sapiens

SUBMITTER: Jorge de la Rosa

PROVIDER: E-GEOD-41799 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptional profiling of human cancer cell lines upon ZMPSTE24 silencing

Project description:Defining the aging-cancer relationship is a challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate many features of aging. However, their short lifespan and cell-intrinsic and -extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. To circumvent these limitations we have generated Zmpste24 mosaic mice. Interestingly, these mice develop normally - revealing cell-extrinsic mechanisms are preeminent in progeria- and display decreased incidence of infiltrating oral carcinomas. Moreover, ZMPSTE24 knock-down reduces human cancer cell invasiveness. Our results disclose the ZMPSTE24-prelamin A system as an example of antagonistic pleiotropy on cancer and aging, support the potential of cell-based and systemic therapies for progeria, and highlight ZMPSTE24 as a new anticancer target.

2014-06-01 | GSE41799 | GEO

Expression data from wild-type and Zmpste24-/- mouse embryonic fibroblasts (MEFs) at an early passage (passage 3, P3)

Project description:Zmpste24 is a metalloproteinase processing prelamin A into mature lamin A, a nuclear structure protein. Zmpste24-/- mice which accumulate prelamin A in cells recapitulate accelerated aging phenotypes observed in human premature aging disorder, Hutchinson Gilford progeria sydrome (HGPS). Zmpste24-/- mouse embryonic fibroblasts (MEFs) exhibited genomic instabiliy and accelerated aging at cellular level, which is premature senescence. We performed microarray analysis on Zmpste24-/- MEFs, compared to wild-type littermates' MEFs, at an early passage (P3), which is a pre-symptom stage before cellular senescence occurs in the mutant MEFs, in order to examine gene expression profile and figure out the underneath mechanism triggering the premature aging process.

2010-11-11 | GSE25257 | GEO

Expression data from wild-type and Zmpste24-/- mouse embryonic fibroblasts (MEFs) at an early passage (passage 3, P3)

2010-11-11 | E-GEOD-25257 | biostudies-arrayexpress

Transcriptomic profiling of ZMPSTE24 knockout endothelial cells: implication of endothelial dysfunction in HGPS

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.

2019-11-27 | GSE137501 | GEO

Transcriptional profiling of liver samples from Lmna Gly609Gly knock-in mice

Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. We report herein a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. By using this animal model, we have developed an antisense morpholino–based therapy that prevents the pathogenic Lmna splicing, dramatically reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide–based therapies for treating human diseases of accelerated aging. 6 samples, three from LmnaG609G/G609G mice and three from control Lmna+/+ mice

2012-01-13 | E-GEOD-32609 | biostudies-arrayexpress

Transcriptional profiling of liver samples from Lmna Gly609Gly knock-in mice

2012-01-13 | GSE32609 | 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

Endothelial-to-mesenchymal transition contributes to accelerated atherosclerosis in Hutchinson–Gilford progeria syndrome

Project description:The main goal of this study was to gain insight into the mechanisms underlying phenotypic changes in endothelial cells during atherosclerosis associated with Hutchinson-Gilford progeria syndrome, a premature aging syndrome. To this end, we performed an RNAseq experiment with aortic intima samples from atheroprone mice with ubiquitous and VSMC-specific progeria expression and their corresponding controls.

2024-06-05 | GSE269166 | GEO

The Role of Lkb1 in Mouse Lung Squamous Cell Carcinoma (SCC) Development

Project description:Lung cancer, majorly divided into non-small cell lung cancer (80-85%) and small cell lung cancer (15-20%), is the leading cause of cancer death in USA. Squamous Cell Carcinoma (SCC) is one of major subtypes of non-small cell lung cancer. Although genomic analysis of tumors from SSC patients have identified frequently mutated genes in these tumors, it’s still largely unknown which genes determine SCC development. Now we found that ablation of alone Lkb1 could induce SCC around 12 months of age. Therefore, transcriptome analysis of lung SCC of CCSPiCreLkb1f/f mice will help us understand how Lkb1 regulates the development of lung SCC.

2019-03-01 | GSE111313 | GEO

The Heterochromatin protein 1 is a master regulator in RNA splicing precision deficient in ulcerative colitis

Project description:Defects in RNA splicing have been linked to numerous human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that, in the gut epithelium of patients with ulcerative colitis (UC), the expression of the chromatin and alternative splicing regulator HP1g is strongly reduced. Accordingly, inactivation of the HP1g gene in the mouse gut triggered several IBD-like traits, including inflammation and dysbiosis. In parallel, we discovered that its loss of function broadly increased splicing noise, reducing requirement for canonical splicing consensus sequences, and favoring the usage of cryptic splice sites at numerous genes with key functions in gut biology. This notably resulted in the production of progerin, a noncanonical toxic splice variant of prelamin A mRNA, responsible for the Hutchinson Gilford Progeria Syndrome (HGPS) of premature aging. Likewise, production of progerin transcript was found to be a signature of colonic cells from UC patients. Thus, our study identifies HP1g as a regulator of RNA metabolism in vivo, providing a unique mechanism linking anti-inflammation and accuracy of RNA splicing in the gut epithelium. HP1 defect may confer a general disturbance in RNA splicing precision to scrutinize in IBD and more generally in accelerating aging diseases.

2022-10-25 | PXD031580 | Pride

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