RNA-Seq in senescent cells with restored levels of TRF2
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE160503 | GEO | 2022/06/27
REPOSITORIES: GEO
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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
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
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.
2015-04-20 | GSE56892 | GEO
Project description:Telomeres, the nucleoprotein structures located at the end of eukaryotic DNA, protect chromosomal integrity. These structures undergo changes during development and aging, including length shortening and alterations in the levels of the proteins associated to them called shelterin, all this affecting genome stability as the cells age. However, telomeres also behave as transcriptional regulators acting not only on genes present at subtelomeres but also on more distantly located genes presented throughout the genome. This process is referred as Telomere Position Effect (TPE). Here we set to determine whether telomere shortening in senescent cells impact TPE and senescent cells transcriptome. We also investigate whether TRF2 (a shelterin protein) and Lamin B1 (a member of nuclear lamina) are involved in TPE by doing RNA sequencing of young and senescent cells in which we modulated TRF2 and Lamin B1 expression.
2023-03-02 | GSE180406 | GEO
Project description:RNA-Seq in senescent cells with restored levels of TRF2
| PRJNA673412 | ENA
Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.
2023-10-22 | PXD031416 | Pride
Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.
2023-10-21 | PXD024630 | Pride
Project description:Background: The Telomeric Repeat binding Factor 2 (TRF2), a key protein involved in telomere integrity, is over-expressed in several human cancers and promotes tumor formation and progression. Recently, TRF2 has been also found outside telomeres where it can affect gene expression. Here we provide evidence that TRF2 is able to modulate the expression of microRNAs (miRNAs), small non-coding RNAs altered in human tumors. Among the miRNAs regulated by TRF2, we focused on the miR-193b-3p, an oncomiRNA that positively correlates with TRF2 expression in human colorectal cancer patients. At the mechanistic level, the control of miR-193b-3p expression requires the cooperative activity between TRF2 and the chromatin organization factor CTCF. We found that CTCF physically interacts with TRF2, thus driving the proper positioning of TRF2 on a binding site located upstream the miR-193b-3p host-gene. The binding of TRF2 on the identified region is necessary for promoting the expression of miR-193b3p which, in turn, inhibits the translation of the onco-suppressive methyltransferase SUV39H1 and promotes tumor cell proliferation. The translational relevance of the oncogenic properties of miR-193b-3p was confirmed in patients, in whom the association between TRF2 and miR-193b-3p has a prognostic value.
2022-03-17 | GSE186022 | GEO
Project description:Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a nontelomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S-mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons, and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release.
2015-11-06 | GSE72887 | GEO
Project description: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.
2006-11-21 | E-MEXP-141 | biostudies-arrayexpress