Premature senescence and increased oxidative stress in the thymus of Down Syndrome patients
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA702748 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13736900_1.fastq.gz | Fastqsanger.gz | |||
| SRR13736900_2.fastq.gz | Fastqsanger.gz | |||
| SRR13736901_1.fastq.gz | Fastqsanger.gz | |||
| SRR13736901_2.fastq.gz | Fastqsanger.gz | |||
| SRR13736902_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 48 |
Similar Datasets
Project description:Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in down syndrome (DS) patients, normally seen in older healthy subjects. We then performed RNA-Seq analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased -galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage.
2021-12-24 | GSE167021 | GEO
Project description:Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased β-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.
| S-EPMC8204718 | biostudies-literature
Project description:Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in post mortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (>200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (>4-fold) and p16INK4A (up to 2-fold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater -amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for -amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
2024-04-26 | GSE264648 | GEO
Project description:Sirtuins are deacetylases or ADP-ribosyltransferases which are implicated in multiple pathways involved in metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4, which overexpression negatively impacts on mitochondrial oxidative capacity, with premature senescence and skin aging. Accordingly, SIRT4 mRNA levels were significantly increased in vitro in human dermal fibroblasts after repetitive UVB exposure or in senescence triggered by mitotic spindle stress or ionizing radiation. Similarly, analysis of SIRT4 expression in vivo in human skin revealed upregulation of SIRT4 mRNA levels in the dermal compartment of photaged skin as compared with the dermis of intrinsically aged skin. In all our in vitro models, upregulation of SIRT4 expression was associated with decreased levels of miR-15b. Also, in human skin, highest copy numbers of miR-15b mRNA were detected in the epidermis, and epidermal expression was significantly reduced in photoaged skin as compared with intrinsically aged skin. Reduced miR-15b expression is most likely causally linked to increased SIRT4 expression because we found that (i) miR-15b displays a conserved and direct binding site within the 3'-untranslated region of the SIRT4 gene as demonstrated by luciferase reporter assays and (ii) transfection of oligonucleotides mimicking miR-15b function was sufficient to prevent SIRT4 upregulation in senescent cells in vitro. Thus, we propose that miR-15b acts as a negative regulator of SIRT4 expression to antagonize mitochondrial dysfunction and hence cellular senescence as well as tissue aging, in particular photoaging of the skin.
2016-06-08 | GSE45729 | GEO
Project description:Recently, senescence has been suggested as a defense mechanism to block sporadic induction of cancer cells. Radiation treatment induces proliferating cancer cells to turn into non-proliferating senescent cells in vitro. To characterize transcriptional reprogramming after radiation treatment, we measured the gene expression profiles of MCF7 at different time points after treatment. In these experiments, we found that IR induced premature senescence in MCF7 cells, and IR treatment resulted in significant changes in the expression of 305 marker genes (less than 1% FDR), which were strongly correlated (|r|>0.9) with IR treatment in a time-dependent manner. Functional analysis of these markers indicated that the dynamics of cytoskeletal structure and lysosomal activity gradually increased. The expression of marker genes for modulator proteins, that were responsible for the dynamics of actin stress fibers and focal adhesion, displayed a particularly strong positive correlation with senescence-associated (SA) morphological changes through time. We also observed a strong induction of genes related to lysosomal metabolic activity, which was accompanied by an increase in the number of SA-beta-Gal positive cells. However, the expression of genes for the cell cycle progression, the post-transcription and the translation activities gradually decreased after radiation treatment. Especially, we observed clear cell cycle arrest specifically at the S and G2/M phases with consistent down-regulation of genes for microtubule assembly/disassembly or spindle biogenesis. Gene expression profiles were obtained from human MCF7 cells after ionizing radiation (6 Gy) at day 0 (no ionizing radiation), day 1 (after ionizing radiation), day 2, day 3, and day 4.
2010-06-08 | E-GEOD-21748 | biostudies-arrayexpress
Project description:To investigate the function of NAC094 in vivo, we overexpressed NAC094 in the infected cells of nodules using an L. japonicus Lb2 expression cassette. To this end, we used a GUS overexpression construct as control and analysed stably transformed plants to detect symbiotic phenotypes. Results show that overexpression of NAC094 causes premature senescence of nodules. To identify the mechanism by which NAC094 regulates nodule senescence, we performed a transcriptome profiling analysis of nodules at 3 wpi. Around 13,850 differentially expressed genes (DEGs) were identified by comparing NAC-OE with control nodules (Log2FC > 1, FDR < 0.05). Of these, 7,516 were up-regulated (NAC-OE-UP) and 6,334 were down-regulated (NAC-OE-DOWN).
2023-03-23 | GSE197361 | GEO
Project description:Oxidative stress is a primary cause of cellular senescence and contributes to the pathogenesis of numerous human diseases. Oxidative damage to telomeric DNA is proposed to trigger premature senescence by accelerating telomere shortening. Here we tested this model directly using a precision tool to produce the common base lesion 8-oxoguanine (8oxoG) exclusively at telomeres in human fibroblast and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and delayed mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions which drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.
2022-05-26 | GSE175686 | GEO
Project description:Protein acyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer, and its elevated expression correlates with diminished survival not only in human breast cancer but also in six other cancer types. In a direct demonstration of pro-tumor DHHC3 function, ZDHHC3 ablation diminished both MDA-MB-231 mammary cell xenografts growth and the size of metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. Consistent with increased senescence, ZDHHC3-ablated tumors showed enhanced recruitment of innate immune cells (anti-tumor macrophages, NK cells) associated with clearance of senescent tumors. ZDHHC3-ablation effects (decreased tumor growth, increased oxidative stress, increased senescence) were reversed upon reconstitution with wildtype, but not enzyme active site-deficient DHHC3. ZDHHC3-ablation effects on oxidative stress/senescence were also substantially reversed upon concomitant ablation of upregulated oxidative stress driver TXNIP. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely plays a key role in TXNIP upregulation. In conclusion, through its palmitoylation activity, DHHC3 supports in vivo breast tumor growth by a mechanism involving negative modulation of tumor cell oxidative stress and senescence.
2017-08-18 | GSE102776 | GEO
Project description:Stem cell therapy requires massive scale homogeneous stem cells under strictly qualification control. However, Prolonged ex vivo expansion impairs the biological functions and results in senescence of mesenchymal stem cells (MSCs). We investigated the function of CTDSPL in premature senescence process of MSCs and clarified that miR-18a-5p played a prominent role in preventing senescence of long-term cultured MSCs and promoting the self-renew ability of MSCs. Inhibition of miR-18a-5p promoted the expression of CTDSPL and induced premature senescence of MSCs. Continuous overexpression of miR-18a-5p improved self-renewal of MSCs by reduced ROS level, increased expression of Oct4 and Nanog, promoted growth rate and differentiation capability. We reported for the first time the dynamic interaction of miR-18a-5p and CTDSPL is crucial for stem cell senescence.
2022-09-04 | GSE212185 | GEO
Project description:Recently, senescence has been suggested as a defense mechanism to block sporadic induction of cancer cells. Radiation treatment induces proliferating cancer cells to turn into non-proliferating senescent cells in vitro. To characterize transcriptional reprogramming after radiation treatment, we measured the gene expression profiles of MCF7 at different time points after treatment. In these experiments, we found that IR induced premature senescence in MCF7 cells, and IR treatment resulted in significant changes in the expression of 305 marker genes (less than 1% FDR), which were strongly correlated (|r|>0.9) with IR treatment in a time-dependent manner. Functional analysis of these markers indicated that the dynamics of cytoskeletal structure and lysosomal activity gradually increased. The expression of marker genes for modulator proteins, that were responsible for the dynamics of actin stress fibers and focal adhesion, displayed a particularly strong positive correlation with senescence-associated (SA) morphological changes through time. We also observed a strong induction of genes related to lysosomal metabolic activity, which was accompanied by an increase in the number of SA-beta-Gal positive cells. However, the expression of genes for the cell cycle progression, the post-transcription and the translation activities gradually decreased after radiation treatment. Especially, we observed clear cell cycle arrest specifically at the S and G2/M phases with consistent down-regulation of genes for microtubule assembly/disassembly or spindle biogenesis.
2010-05-31 | GSE21748 | GEO