The mTOR pathway is necessary for survival of mice with short telomeres.
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ABSTRACT:
PROVIDER: PRJNA524859 | ENA |
REPOSITORIES: ENA
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Project description:The factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, known to decrease with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact M-NM-2-cell mass. Islets from mice with short telomeres displayed evidence of M-NM-2-cell dysfunction, and in response to glucose, had defective mitochondrial membrane depolarization as well as Ca2+ handling which limited insulin release. Short telomeres induced the hallmarks of senescence including premature accumulation of p16INK4a, and altered gene expression of key pathways essential for signaling and insulin secretion. Short telomeres also had an additive damaging effect to endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This manifested as more severe hyperglycemia in insulin mutant Akita mice which had a more profound loss of M-NM-2-cell mass and increased M-NM-2-cell apoptosis. Our data identify impaired signaling in the setting of senescence as a novel mechanism of telomere-mediated disease, and implicate telomere length as a determinant of risk and pathogenesis in diabetes. The experiment is designed to analyze gene expression profiles of islets from mice with short telomeres compared to those of wildtype mice.
2013-10-01 | E-GEOD-25040 | biostudies-arrayexpress
Project description:The factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, known to decrease with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. Islets from mice with short telomeres displayed evidence of β-cell dysfunction, and in response to glucose, had defective mitochondrial membrane depolarization as well as Ca2+ handling which limited insulin release. Short telomeres induced the hallmarks of senescence including premature accumulation of p16INK4a, and altered gene expression of key pathways essential for signaling and insulin secretion. Short telomeres also had an additive damaging effect to endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This manifested as more severe hyperglycemia in insulin mutant Akita mice which had a more profound loss of β-cell mass and increased β-cell apoptosis. Our data identify impaired signaling in the setting of senescence as a novel mechanism of telomere-mediated disease, and implicate telomere length as a determinant of risk and pathogenesis in diabetes.
2013-10-01 | GSE25040 | GEO
Project description:Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc-/-) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc-/- livers. Treatment of G2-Terc-/- mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc-/- mice also decreases longevity, in contrast to lifespan extension in single S6K1-/- female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.
| S-EPMC7054554 | biostudies-literature
Project description:Gene expression profiles of Terc+/+ and generation 2 (G2) Terc-/- male mice fed rapamycin or control diet during 2 months. Rapamycin diet contains encapsulated rapamycin at 42 ppm (mg of drug per kg of food); control diet contains coating material (Eudragit S100). Rapamycin was microencapsulated by Rapamycin Holdings Inc. (San Antonio, Texas) and was then incorporated into 5LG6 mouse chow (TestDiet, London, UK).
2020-01-02 | GSE127475 | GEO
Project description:We sorted H2O2–treated HCC Huh7-cells harboring telomeres in the top 20th percentile (long telomeres) and bottom 20th percentile of telomere length (short telomeres) according to fluorescence-activated cell sorting based on the fluorescence intensity associated with the telomere-binding protein, followed by whole-genome mRNA-expression microarray analysis. In detail, a stable Huh7 cell line expressing GFP-tagged telomere-binding protein adrenocortical dysplasia protein homolog (TPP1) was established using 1 mg/mL G418 as a selection antibiotic. The telomere lengths in living cells were measured by assessing the expression of TPP1 by fluorescence-activated cell sorting (FACS) under the assumption that the expression level of the telomere binding protein is proportional to telomere length. The cells were dissociated at 37°C in 0.2 % w/v trypsin-EDTA for 10 min. After gentle pipetting to induce dissociation, the cells were washed twice with cold PBS solution containing 0.6 % w/v ultra-pure bovine serum albumins (A0100-010) and filtered using a cell strainer (BD Bioscience). HCC cells displaying weak or strong GFP expression were isolated from the mock- or H2O2-treated cells using a FACS Aria II (BD Bioscience), respectively. A whole genome mRNA expression microarray (Macrogen, Seoul, Korea) was used to compare the gene expression patterns between HCC cells possessing short or long telomeres.
2019-06-10 | GSE114004 | GEO
Project description:In our previous study, mice with pulmonary fibrosis induced by a bleomycin insult in the context of short telomeres develop pulmonary fibrosis. By using AAV9 vectors carrying the telomerase Tert gene to treat those mice, we explore the possibility of telomerase gene therapy as a possible treatment for IPF patients carrying short telomeres. To further understand gene expression changes undergoing in ATII cells upon telomerase activation, we isolated ATII cells from pulmonary fibrosis Tert-treated and empty vector-treated lungs at 1 week after AAV9 inoculation by FACS.
2018-01-22 | GSE93869 | GEO
Project description:Gene expression profile of Huh7 cells with long and short telomeres
| PRJNA454861 | ENA
Project description:Mitochondrial carrier homolog 2 (MTCH2) is necessary for AML survival
| PRJNA615031 | ENA
Project description:At critically short telomeres TERRA RNA-DNA hybrids become stabilized and drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. Here, we report that hybrids at telomeres prevent resection by the Exo1 nuclease when telomeres become non-functional. We employed the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. These results give insights into an additional role of TERRA at dysfunctional telomeres suggesting that it not only affects replicative senescence rates through HDR activation at critically short telomeres, but may also affect resection rates at intermediate length telomeres in pre-senescent cells.
2023-01-18 | PXD034986 | Pride
Project description:Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to identify telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple RNA biogenesis processes. Using Chromatin- and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates to telomeres in an R-loop dependent manner, as changes in R-loop levels, e.g. at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches we demonstrate that Npl3 binds to TERRA and stabilizes R-loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.
2020-01-31 | PXD016772 | Pride