Global landscape mapping of chromatin accessibility in DNA damage-induced senescent human stromal cells
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PROVIDER: PRJNA559076 | ENA |
REPOSITORIES: ENA
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Project description:We report the application of an improved assay for transposase-accessible chromatin with high-throughput sequencing in profiling changes of chromatin openning state in senescent human stromal cells. By obtaining over four billion bases of sequence from Tn5 transposase-processed chromosome DNAs, we generated genome-wide chromatin-state maps of human primary stromal cells (with a starting cell number of 50,000). This study provides a framework for the application of ATAC-Seq technique towards spatiotemporal chromatin configuration of human stromal cells upon DNA damage-induced senescence.
2021-03-23 | GSE135481 | GEO
Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
2023-06-01 | GSE153683 | GEO
Project description:Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole genome transcriptional profiling and compared senescent fibroblasts to their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNAi did not impact senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, demonstrating that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we demonstrate that OPN is expressed in senescent stroma within preneoplastic lesions that arise following DMBA/TPA treatment of mice, suggesting that stromal-derived OPN-mediated signaling events impact neoplastic progression.
2009-03-30 | GSE13330 | GEO
Project description:mRNA expression profiling of DNA damage-induced senescent cells
| PRJNA714876 | ENA
Project description:Senescent cells secrete many molecules, which contribute to the prevention of cancer progression. We induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. The first two are considered inducers of acute senescence while extensive proliferation triggers replicative senescence also named chronic senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC conditioned media and evaluated proliferation, DNA damage, apoptosis and senescence.
2018-10-25 | PXD003018 | Pride
Project description:Aging and age-related pathologies can be delayed by specifically targeting the senescence-associated secretory phenotype (SASP), a hallmark feature of senescent cells. Achieving the goal using natural or synthetic agents would have a tremendous impact on the quality of lifespan and burden of age-related chronic diseases. We report the potential of rutin, a bioactive phytochemical component derived from natural plants specifically ginkgo boliva, in targeting senescent cells via suppression of the SASP. This study demonstrates the efficacy of rutin as medicinal agent in controlling the influence of senescent human stromal cells and provides a strong rationale for its future use in aging intervention and geriatric medicine.
2023-11-02 | GSE190279 | GEO
Project description:Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole genome transcriptional profiling and compared senescent fibroblasts to their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNAi did not impact senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, demonstrating that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we demonstrate that OPN is expressed in senescent stroma within preneoplastic lesions that arise following DMBA/TPA treatment of mice, suggesting that stromal-derived OPN-mediated signaling events impact neoplastic progression. Experiment Overall Design: Human foreskin BJ fibroblasts were mock or Bleomycin sulfate-treated (100ug/ml, Sigma, St. Louis, MO) for 24 hrs. Replicatively senescent fibroblasts were obtained by continuous passage. After 72 hr serum-starvation, RNA was collected using TRIzol (Invitrogen, Carlsbad, CA). Biotinylated cRNA was hybridized to Affymetrix Human Genome U133 Plus 2.0 GeneChips (Affymetrix, Santa Clara, CA) by the Washington University Microarray Facility. Experiment Overall Design: There were 4, 6, and 6 samples for SIPS, RS, and young respectively: Experiment Overall Design: - Stress-induced premature senescence (GSM336347..GSM336379) Experiment Overall Design: - Replicative Senescent (GSM336385..GSM336573) Experiment Overall Design: - Young (GSM336574..GSM336628) Experiment Overall Design: Microarray quality control, analysis, and clustering (UPGMA by Centroid) were performed using dChip (May, 2008 release). All GeneChip comparisons had a cut-off basis of a lower bound of 90% confidence of fold-change â?¥1.5 and expression intensity difference â?¥75.
2009-04-04 | E-GEOD-13330 | biostudies-arrayexpress
Project description:The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. We discovered that H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. Knock-down of H2A.J interfered with the derepression of a set of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over-expression of H2A.J increased the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signaling of senescent cells to the immune system. 41 samples analysed
2016-07-04 | E-GEOD-62701 | biostudies-arrayexpress
Project description:Expression data from thymic non-hematopoietic stromal cells after damage
| PRJNA418718 | ENA
Project description:Cellular senescence is accompanied by profound changes in telomere and heterochromatin structure that contribute to ageing. Telomere shortening is a key driver of replicative senescence that activate DNA damage response signaling ending on a p53-dependent downregulation of the shelterin subunit TRF2. Restoring the levels of TRF2 in pre-senescent cells leads to delay entry into senescent and restoration of constitutive heterochromatin structure and damage. Here we set to determine whether the restoration of TRF2 levels change the senescent program by doing RNA-sequencing of senescent cells transduced with a TRF2-expressing lentivirus or an empty lentivirus control.
2022-06-27 | GSE160503 | GEO