Gene expression data in mouse whole lung
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE114005 | GEO | 2018/11/28
REPOSITORIES: GEO
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Project description:The mechanisms that regulate pluripotency and cell fate are still largely unknown. Here, we show that the Telomere Repeat Binding Factor 1 (TRF1), a component of the shelterin telomere protection complex, regulates genome-wide binding of polycomb to stem cell and pluripotency genes, thereby exerting vast epigenetic changes that contribute to maintain embryonic stem cells in a naïve state. We further show that TRF1 mediates these effects by regulating TERRA, the long-non-coding RNAs transcribed from telomeres and that are part of the telomeric chromatin. In particular, we find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and a higher binding of TERRA to those genes, an event that is coincidental with TRF1-dependent induction of cell-fate programs and loss of the naïve state. These results are consistent with a model in which TERRA recruits polycomb to genes important for pluripotency and differentiation in a manner that is dependent on TRF1. These unprecedented findings explain the long-standing observation that TRF1 is one of the most upregulated genes during induction of pluripotency and it is essential for the induction and maintenance of pluripotency.
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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.
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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.
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Project description:Tubulointerstitial fibrosis associated to chronic kidney disease represents a global healthcare problem. We showed previously that short and dysfunctional telomeres lead to interstitial renal fibrosis, however, the cell-of-origin of kidney fibrosis associated to telomere dysfunction was unknown to date. To identify the specific cell type responsible for this type of renal fibrosis, we induced telomere dysfunction by deleting the Trf1 telomere-binding factor both in renal fibroblasts and pericytes both in short-term and long-term life-long experiments in mice. Short-term Trf1 deletion in renal fibroblasts and pericytes was not sufficient to trigger kidney fibrosis. However, long-term persistent deletion of Trf1 in fibroblasts, triggered inflammation, cell cycle arrest, fibrogenesis, and vascular rarefaction. These cellular responses lead to macrophage-to-myofibroblast transition (MMT), Endothelial-to-mesenchymal transition (EndMT), and epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at humane-endpoint when deletion of Trf1 in fibroblasts was maintained throughout the lifespan of mice. In contrast, Trf1 deletion in pericytes did not lead to any kidney phenotypes both in short-term and long-term experiments.
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Project description:Telomeric Repeat-containing RNA are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the Heterochromatin Protein 1protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed mammalian genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblastsderiving from 13.5 embryonic day embryos compared to their littermate controls. We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA Immunoprecipitation. Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNARNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.
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Project description:Telomeres play crucial roles during tumorigenesis inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alters telomeric chromatin composition and function. Here we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveals upregulation of proteins involved in chromatin remodeling, DNA repair and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.
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Project description:The naked mole rat (NMR), a long-lived and cancer resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by the NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment.
2021-03-02 | GSE163064 | GEO
Project description:Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells. It is a multifunctional protein involved in deubiquitination, ubiquitination, and ubiquitin homeostasis. UCHL1 has been associated with various diseases, including many cancers, but its specific roles are disputed and still generally undetermined. Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and TERF2IP, also a component of the shelterin complex, were bound to the nuclear scaffold. UCHL1 may play a role in regulating gene expression by affecting the stabilization of the shelterin proteins or influencing nuclear targeting. As several shelterin proteins (TRF1, TRF2, POT1 and TERF2IP) are ubiquitinated, UCHL1 may have a role in regulating the stability of these proteins. UCHL1 may also regulate the nuclear location of shelterin-associated genomic regions.
2018-02-23 | GSE97111 | 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. 6 total samples were analysed. Three were from control samples that were heterozygous for Trf2 and three samples had Trf2 deleted.
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Project description:Telomeric repeat sequences are prone to induce replication stress and one of the core telomere binding proteins, TRF1, is thought to counteract these problems. The molecular mechanisms coming into play upon TRF1 loss were not clearly defined though. This study combines an inducible TRF1 loss with telomere-targeted proteomics to analyze the incurring changes. The results show that loss of TRF1 causes important alterations in telomere associated proteins and the new profile resembles in a number of ways that of cells in which telomeres are maintained by telomerase-independent mechanisms, named ALT. The presence of DNA repair proteins (MRN complex, the SMC5/6 complex), some increases in telomere colocalization with PML bodies, sister chromatid exchanges and clear signs of increased TERRA transcription and mitotic break-induced replication are part of these phenotypes. The data also show that these early ALT phenotypes can be differentiated from drug induced replication stress, and part of this ALT response is conserved in human cells. These studies therefore point to a critical role for TRF1 in preventing the emergence of ALT and hence immortalization of cells. Given that the details for how ALT actually is initiated remained unclear, these findings are an important step forward and will spur new research into that question.
2020-01-22 | PXD017022 | Pride