Homo sapiens
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PROVIDER: PRJNA362620 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic beta cell senescence occurs during the development of Type 1 Diabetes. To model the transcriptional responses of islet cells to DNA damage, we previously developed a human islet culture model in which the DNA damage response and senescence can be induced via double strand-breaks with the agent bleomycin. Here, we report the transcriptome-wide changes in human pancreatic islet cells following bleomycin exposure.
2021-06-08 | GSE176324 | GEO
Project description:Kollarovic2016 - Cell fate decision at G1-S
transition
This model is described in the article:
To senesce or not to
senesce: how primary human fibroblasts decide their cell fate
after DNA damage.
Kollarovic G, Studencka M, Ivanova
L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS,
Schaber J.
Aging (Albany NY) 2016 Jan;
Abstract:
Excessive DNA damage can induce an irreversible cell cycle
arrest, called senescence, which is generally perceived as an
important tumour-suppressor mechanism. However, it is unclear
how cells decide whether to senesce or not after DNA damage. By
combining experimental data with a parameterized mathematical
model we elucidate this cell fate decision at the G1-S
transition. Our model provides a quantitative and conceptually
new understanding of how human fibroblasts decide whether DNA
damage is beyond repair and senesce. Model and data imply that
the G1-S transition is regulated by a bistable hysteresis
switch with respect to Cdk2 activity, which in turn is
controlled by the Cdk2/p21 ratio rather than cyclin abundance.
We experimentally confirm the resulting predictions that to
induce senescence i) in healthy cells both high initial and
elevated background DNA damage are necessary and sufficient,
and ii) in already damaged cells much lower additional DNA
damage is sufficient. Our study provides a mechanistic
explanation of a) how noise in protein abundances allows cells
to overcome the G1-S arrest even with substantial DNA damage,
potentially leading to neoplasia, and b) how accumulating DNA
damage with age increasingly sensitizes cells for
senescence.
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2024-09-02 | BIOMD0000000632 | BioModels
Project description:Fibrosis refers to the abnormal proliferation and excessive accumulation of fibrous tissue in an organ or tissue, typically caused by chronic injury or inflammation. Fibroblasts play a crucial role in the initiation and progression of fibrosis, with their excessive activation and overproduction of ECM being key mechanisms in fibrotic diseases. In this study, we constructed decellularized lung scaffolds from normal mice and bleomycin-induced lung decellularized scaffolds to analyze and compare the differential gene expression in control human fibroblasts, TGFβ-induced human fibroblasts, fibroblasts co-cultured with normal lung decellularized scaffolds, and fibroblasts co-cultured with bleomycin-induced lung decellularized scaffolds. This investigation aims to explore the impact of ECM on fibroblast activation and its underlying mechanisms.
2025-08-20 | GSE275625 | GEO
Project description:For studing dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest, samples were treated with the DNA-damaging agent bleomycin at 0 ug/ml, 2 ug/ml and 40 ug/ml for 2 h. High-resolution time course analysis of gene expression in DNA damage-induced cellular senescence and transient cell-cycle arrest was used to explore the transcriptomic differences between different cell fates after DNA damage response.
2018-03-27 | GSE112068 | GEO
Project description:We have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish Mmp19 regulation of fibroblast phenotype changes in mouse lungs. Pulmonary fibrosis was induced by bleomycin at 0.08 u in 50ul of saline. At 21st day the mice were sacrificed and mouse lung fibroblasts were isolated and cultured in FBM plus additives following Lonza's portocol. RNA was extracted with miRNA mini kit from Qiagen. Gene expression microarray was performed with Agilent. A 834-gene consensus signature was identified that distinguished between Mmp19 knockout mice from wildtype. Some gene expression in the same RNA samples were validtaed by real-time PCR. The established bleomycin induced fibrosis was used in this experiment. At day 21 the fibrosis would be the situation of stable fibrosis. We administrated 0.08u of bleomycin intratracheally into wildtype and Mmp19 knockout mice, sacrificed the mice at 21st day and isolated the lung fibroblasts and culturing. Five independent experiments were performed and 3 for gene expression experiment.
2014-08-05 | E-GEOD-49643 | biostudies-arrayexpress
Project description:Objectives: The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation. Methods: The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRIact-induced skin fibrosis. Results: The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation. Conclusions: Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
2021-12-21 | GSE184356 | GEO
Project description:We conducted fibroblast-specific transcriptome analysis by next generation sequencing in order to investigate qualitative change and activation signatures of lung fibroblasts in bleomycin-induced pulmonary fibrosis. Lung fibroblasts were identified by using reporter mice of collagen-α2(I), in which collagen I-producing fibroblasts were labeled with EGFP. Lungs were dissociated with protease sollution, and single cell suspension were stained with lineage markers (Ter119, CD45, CD31, EpCAM). Lineage- GFP+ cells were sorted out and mRNA was collected. Using serial analysis of gene expression (SAGE) method, we identified 2,973,937 SAGE tags (1,080,798 tags from saline-treated GFP+ fibroblasts and 1,893,139 tags from bleomycin-treated GFP+ fibroblasts). We found that genes related to extracellular matrix construction were highly up-regulated in fibroblasts from belomycin-treated lungs. Moreover, an analysis of mRNA profiles revealed biological functions such as proliferation, invasion, adhesion, and migration were promoted in fibroblasts from bleomycin-treated lung, which recapitulated the role of fibroblasts in the fibrogenesis. These fibroblast-specific gene expression profiles will be important notions in future fibrosis studies. mRNA profiles of Lung fibroblasts from 3 mice at day 14 after saline or bleomycin treatment.
2013-07-22 | E-GEOD-42564 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks. RNA was isolated from human fetal lung fibroblasts, HCT116 p53+/+, or HCT116 p53-/- cells treated with doxorubicin or sham for 26 hours. Human fetal lung fibroblasts were transfected with siRNAs targeting DINO or non-targeting control and subsequently treated with doxorubicin for 26 hours.
2012-11-20 | E-GEOD-42368 | biostudies-arrayexpress
Project description:To analyse the early phase of the transcriptional response to bleomycin-induced damage and its dependence on the severity of the damage, we used exposure for 1 hour to a sub-lethal (0.3 u/l) and a lethal (3 u/l) dose of bleomycin. In addition, an aliquot of the 0.3 u/l treatment was washed free of bleomycin and incubated for an additional 3 hours in its absence. Thereafter total RNA was prepared and transcriptional patterns were determined by SuperSAGE (Molina et al., 2008, BMC genomics 9, 553 and Matsumura et al., 2010, PLOS ONE 5, e12010. The transcriptional response to bleomycin in wild-type and the Ppatm-1, Ppatr-1 and Ppatmatr-1 mutants was analysed as above in a second, separate experiment using the 1 hour pulse treatment with a sub-lethal (0.3 u/l) concentration followed by the 3 hour recovery period .
2020-05-04 | E-MTAB-9082 | biostudies-arrayexpress
Project description:The changes in global gene expression in response to DNA damage may derive from either direct induction or repression by transcriptional regulation or indirectly by synchronization of cells to specific cell cycle phases, such as G1 or G2. We developed a model that successfully estimated the expression levels of >400 cell-cycle-regulated genes in normal human fibroblasts based on the proportions of cells in each phase of the cell cycle. By isolating effects on the gene expression associated with the cell cycle phase redistribution after genotoxin treatment, the direct transcriptional target genes were distinguished from genes for which expression changed secondary to cell synchronization. Application of this model to ionizing radiation (IR)-treated normal human fibroblasts identified 150 of 406 cycle-regulated genes as putative direct transcriptional targets of IR-induced DNA damage. Changes in expression of these genes after IR treatment derived from both direct transcriptional regulation and cell cycle synchronization. Keywords: Microarray, Cell cycle, Ionizing radiation, Human fibroblasts, EPIG
2007-08-01 | GSE7075 | GEO