Subtelomeric CTCF and Cohesin binding site organization using improved subtelomere assemblies and a novel annotation pipeline
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Nicholas Stong
PROVIDER: E-GEOD-55053 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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.
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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.
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Project description:Transcriptionally silent heterochromatin preferentially localizes at the nuclear periphery, but, despite this, certain budding yeast genes relocate to the nuclear periphery following gene activation, implicating the nuclear envelope in both transcriptional activation and silencing. It is unclear how these distinct chromatin domains are established, maintained and distinguished from one another at the nuclear envelope. Here we report that nuclear pore complexes (NPCs) facilitate the transition between chromatin states by providing a platform to which chromatin-remodeling and chromatin-modifying complexes bind. In particular, we show that the RSC chromatin-remodeling complex associates with NPCs and that the nucleoporin Nup170p nucleates heterochromatin formation at telomeres through recruitment of Sir4p. Deletion of NUP170 altered subtelomeric chromatin structure, reduced SIR complex binding at telomeres, impaired telomeric silencing and abated telomere tethering. These results support a model in which telomeric heterochromatin formation occurs through telomere-NPC interactions that both promote Sir4p binding at telomeres and permit chromatin-remodeling complexes to mediate the transition between chromatin states. Examination of genome-wide nucleosome positions in WT and nup170∆ cells via next-generation sequencing of mononucleosomal DNA.
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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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