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Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of acute telomere dysfunction in the mouse liver using adenoviral mediated, transient expression of a dominant negative version of TRF

ABSTRACT: Telomere dysfunction induces two types of cellular responses: cellular senescence and apoptosis. Here we analyzed the influence of the cellular level of telomere dysfunction and the role of p53 on induction of apoptosis and senescence in mouse liver using the experimental system of adenoviral mediated, transient expression of a dominant negative version of TRF2 (TRF2DBDM). Gene-profiling experiments identified p53-dependent and p53-independent changes in gene expression in response to telomere deprotection and transcription factors potentially regulating these genes.

ORGANISM(S): Mus musculus

SUBMITTER: Michael Manns

PROVIDER: E-MEXP-141 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.

Lechel André A Satyanarayana Ande A Ju Zhenyu Z Plentz Ruben R RR Schaetzlein Sonja S Rudolph Cornelia C Wilkens Ludwig L Wiemann Stephanie U SU Saretzki Gabriele G Malek Nisar P NP Manns Michael P MP Buer Jan J Rudolph K Lenhard KL

EMBO reports 20050301 3

Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2delta B delta M). We show that the level of telomere dysfunction correlates with the level of TRF2delta B delta M protein expression resulting in chromosomal fusi ...[more]

PMID: 15723042

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Gene expression data from type II pneumocytes from adult mice with and without Trf2

Project description:Gas exchange in the mammalian lung occurs in the alveolar sacs lined by epithelial cells that form a barrier allowing effective oxygen diffusion. Telomere syndromes have their most common manifestation in degenerative disease of the alveoli, both pulmonary fibrosis and emphysema. We tested the role of telomere dysfunction by inducing deletion of the telomere binding protein Trf2 in type 2 alveolar epithelial cells (AEC2s) that both express the gene encoding surfactant protein C and constitute the regenerative compartment of the alveolar epithelium. Acquired telomere dysfunction in these cells preferentially induced cellular senescence, and mouse lungs were marked by an inflammatory response even though the telomere dysfunction was restricted to the epithelium. Senescent AECs had altered gene expression that differentially fell in inflammatory cell signaling pathways. Bleomycin challenge was uniformly fatal, and Trf2-depleted cells failed to generate clonal alveolar colonies in vitro. The telomere dysfunction response in AEC2s was in part p53-dependent, and we found evidence of a p53-mediated paracrine survival signal to the mesenchyme. These data indicate that telomere dysfunction in the alveolar epithelium limits its regenerative capacity and is sufficient to induce inflammation. It may thus be a primary driving event in telomere-mediated lung disease. Efforts to restore epithelial regenerative capacity may be an effective approach in a subset of fibrosis and emphysema patients. We studied the gene expression changes in adult type II pneumocytes 7 days after deleting Trf2. Mice carried floxed allele of Trf2 and mTmG reporter allele. Type II pneumocytes were collected by FACs sorting GFP+ cells from lungs 7 days after administering tamoxifen. 6 total samples were analysed. Three were from control samples that were heterozygous for Trf2 and three samples had Trf2 deleted.

2015-04-20 | E-GEOD-56892 | biostudies-arrayexpress

Transcriptional profiling of senescent A549 cells

Project description:Telomere dysfunction is the most common identifiable cause of pulmonary fibrosis. Cellular senescence of epithlial cells is thought to play a signfiicant role in disease pathogensis. We established a model of cellular senescence using a human alveolar epithelilial-like cell lines (A549) and profiled the transcriptional changes that occur in response to telomere dyfunction. Telomere dysfunction was induced by expressing a dominant-negative form TRF2, the shelterin binding protein.

2021-01-13 | GSE155941 | GEO

Gene expression data from type II pneumocytes from adult mice with and without Trf2

2015-04-20 | GSE56892 | GEO

RNA-Seq in senescent cells with restored levels of TRF2

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

ZNF365 promotes stability of fragile sites and telomeres

Project description:Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites (CFS) including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange (T-SCE) and formation of anaphase DNA bridges, including ultra-fine DNA bridges (UFB), and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53-ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction. We expressed an inducible p53 allele encoding a p53-estrogen receptor fusion protein (p53ER) that becomes functional upon addition of 4-hydroxytamoxifen (4-OHT) in TKO cells. We chose a time point of 4 hours post-4-OHT induction to catalog potential direct targets.

2013-08-01 | E-GEOD-44599 | biostudies-arrayexpress

ZNF365 promotes stability of fragile sites and telomeres

2013-08-01 | GSE44599 | GEO

TRF2 Inhibition-Mediated Degradation Derepresses the Neuronal Differentiation Program

Project description:Telomere binding factor 2 (TRF2), is a protein that plays a major role in the maintenance of telomere integrity. In mitotic normal and transformed cells, TRF2 inhibition triggers a rapid telomere DNA damage response that results in cell senescence or apoptosis. Here we provide evidence that TRF2 plays a role suppressing neuronal differentiation. TRF2 interacts with the RE1-silencing transcription factor (REST) in nuclear PML protein-containing compartments of neuronal cells in vivo. Inhibition of TRF2 function with a dominant-negative form of TRF2 elicits a telomeric DNA damage response, and disrupts the TRF2-REST complex resulting in proteasomal degradation of REST. Overexpression of REST impairs the ability of DN-TRF2 to induce neuronal differentiation, indicating that enhanced degradation of REST is sufficient to account for the differentiation-inducing effect of DN-TRF2. REST degradation derepresses RE1-regulated genes (L1CAM, BDNF, b3-tubulin, syntaxin and others) resulting in morphological and functional differentiation of neurons. Our findings identify a novel interaction between the telomeric protein TRF2 and REST which regulates the molecular differentiation program of neurons. Keywords: transfection and molecular inhibition

2007-07-01 | GSE6983 | GEO

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [Ribo-seq]

Project description:Abstract：Our previous study found that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs and MLE-12 cells. Further research showed that 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis found 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation and cellular senescence. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable in TRF2 degradation and cellular senescence in pulmonary epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.

2023-12-31 | GSE251659 | GEO

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [RNA-seq]

2023-12-31 | GSE251884 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1

Project description:Telomere erosion contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide screen to identify gene deletions that sensitized p53-positive human cells to loss of telomere integrity, and uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1: TAPR1. CRISPR-Cas9 mediated deletion of TAPR1 led to elevated p53 and induction of p53 transcriptional targets. TAPR1-disrupted cells exhibited a synthetic-sick relationship with the loss of telomerase, or treatment with the topoisomerase II inhibitor doxorubicin. Stabilization of p53 with nutlin-3a further decreased cell fitness in cells lacking TAPR1 or telomerase, whereas deletion of TP53 rescued the decreased fitness of TAPR1-deleted cells. We propose that TAPR1 regulates p53 turnover, thereby tapering the p53-dependent response to telomere erosion. We discuss the possible implications of such a mechanism in the preservation of genome integrity during senescence or aging.

2021-03-04 | PXD022128 | Pride

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