Expression data from wild-type and Zmpste24-/- mouse embryonic fibroblasts (MEFs) at an early passage (passage 3, P3)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25257 | GEO | 2010/11/11
SECONDARY ACCESSION(S): PRJNA134685
REPOSITORIES: GEO
Similar Datasets
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. Early passage wild-type and Zmpste24-/- MEFs were collected for RNA extraction, the quality of RNAs were determinded by Electrophoresis Assay (2100 Bioanalyzer, Agilent) and RNA extractions were used for hybridization on Affymetrix microarrays.
2010-11-11 | E-GEOD-25257 | biostudies-arrayexpress
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
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. 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.
2014-06-01 | E-GEOD-41799 | biostudies-arrayexpress
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
Project description:In this study, we employed massively parallel sequencing technology to identify miRNAs expressed in Zmpste24 WT MEF and Zmpste24-/- MEF. With data from 19.5 ×106 reads from WT MEFs and 16.5 × 106 reads from Zmpste24-/- MEFs, we discovered a total of 306 known miRNAs expressed in MEFs with a wide dynamic range of read counts ranging from 10 to over 1 million. A total of 8 miRNAs were found to be significantly down-regulated, with only 2 miRNAs upregulated, in Zmpste24-/- MEFs as compared to WT MEFs.
2014-12-30 | GSE46379 | GEO
Project description:Idiopathic pulmonary fibrosis is a devastating aging-associated disease of unknown etiology. Despite that aging is a major risk factor, the mechanisms linking aging with this disease are uncertain, and experimental models to explore them in lung fibrosis are scanty. We examined the fibrotic response to bleomycin-induced lung injury in Zmpste24-deficient mice, which exhibit nuclear lamina defects developing accelerated aging. We found that young WT and Zmpste24(-/-) mice developed a similar fibrotic response to bleomycin. Unexpectedly, while old WT mice developed severe lung fibrosis, accelerated aged Zmpste24-/- mice were protected showing scant lung damage. To investigate possible mechanisms associated with this resistance to fibrosis, we compared the transcriptome signature of the lungs and found that Zmpste24(-/-) mice showed downregulation of several core and associated matrisome genes compared with WT mice. Interestingly, some microRNAs that target extracellular matrix molecules such as miR23a, miR27a, miR29a, miR29b-1,miR145a, and miR491 were dysregulated resulting in downregulation of profibrotic pathways such as TGF-β/SMAD3/NF-κB and Wnt3a/β-catenin signaling axis. These results indicate that the absence of Zmpste24 in aging mice results in impaired lung fibrotic response after injury, which is likely associated to the dysregulation of fibrosis-related miRNAs. Aging is a driving force of pulmonary fibrosis. Mice laking Zmpste24 have an accelerated aging phenotype. During the development of the disease there are several extracellular matrix genes, principally collagens upregulated. We use microarray to unveil changes associated with the pulmonary response in aged mice
2018-12-04 | GSE123293 | GEO
Project description:Global heterochromatin reduction, which is one of the hallmarks of aging cells, is associated with reduced transposable element repression and increased risk of chromatin instability. To ensure genomic integrity, the irreparable cells in a population exit permanently from the cell cycle, and this process is termed “senescence”. However, senescence only blocks the expansion of unwanted cells, and the aberrant chromatin of senescent cells remains unstable. Serendipitously, we found that the transient ectopic expression of a repressive epigenetic modulator, DNA methyltransferase 3-like (DNMT3L) was sufficient to delay the premature senescence progression of late-passage mouse embryonic fibroblasts (MEFs) associated with a tightened global chromatin structure. DNMT3L induces more repressive H3K9 methylation on endogenous retroviruses and downregulates the derepressed transposons in aging MEFs. In addition, we found that a pulse of ectopic DNMT3L resulted in the reestablishment of H3K27me3 on polycomb repressive complex 2 (PRC2)-target genes that were derepressed in old MEFs. We demonstrated that ectopic DNMT3L interacted with PRC2 in MEFs. Our data also suggested that ectopic DNMT3L might guide PRC2 to redress deregulated chromatin regions in aging cells. This study might lead to an epigenetic reinforcement strategy for overcoming aging-associated epimutation and senescence.
2019-08-02 | GSE135258 | GEO
Project description:Patients with progeroid syndromes like mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD), harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for post-translational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation, however, efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation which improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with homozygous null mutation in ZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from RD fibroblasts suggest that prelamin A accumulation by itself may not be detrimental.
| MSV000080191 | MassIVE
Project description:Cellular senescence is induced by multiple stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and thus limiting lifespan. The endoplasmic reticulum ITPR2 release channel and calcium fluxes from the ER to the mitochondria have been identified as drivers of cellular senescence in human cells. Here we show that Itpr2 knockout mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in both Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and forced contacts between these two organelles induce premature senescence in normal cells. These new findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and physiological aging.
2019-11-06 | GSE139982 | GEO
Project description:We compared the transcriptomes of isogenic diploid fibroblasts expressing progerin or elevated levels of wild-type prelamin A with that of wild-type fibroblasts. We subsequently used the reversion towards normal of two phenotypes, reduced cell growth and dismorphic nuclei, by treatment with farnesyltransferase inhibitor (FTI) or overexpression of ZMPSTE24, as a filtering strategy to identify genes linked to the onset of these two phenotypes. We carried out microarray analyses of gene expression profiling in isogenic fibroblasts lines to identify the subset of genes whose expression patterns are strongly altered upon expression of progerin or elevated levels of wild-type lamin A. A filtering strategy was then used to identify potential key effectors. We searched for genes whose expression was reverted towards normal by treatment with farnesyl transferase inibitors (FTI) in both cell lines for 48 hours, or by overexpression of ZMPSTE24 in cells with elevated levels of prelamin A, conditions that improve cell proliferation and leads to a significant decrease in nuclear membrane abnormalities.
2012-08-31 | E-GEOD-40404 | biostudies-arrayexpress