Genome-wide maps of RAP1 binding sites.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE20867 | GEO | 2010/07/10
SECONDARY ACCESSION(S): PRJNA124659
REPOSITORIES: GEO
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Project description:By performing chromatin immunoprecipitation coupled with ultra-high-throughput sequencing (ChIP-seq), we find that RAP1 binds to telomeres as well as to extra-telomeric sites through the (TTAGGG)2 consensus motif. Extra-telomeric RAP1 binding sites are particularly abundant at subtelomeric regions, and this is in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. Significantly, more than 70% of extratelomeric RAP1 binding sites are located in the vicinity of known genes and about 40% of the genes deregulated in Rap1-null cells contain binding sites for RAP1, suggesting a role of RAP1 in transcriptional control. Examination of RAP1 binding by CHIP-seq in two independent wild-type mefs using as negative control two independent RAP1-deleted mefs
2010-07-10 | E-GEOD-20867 | biostudies-arrayexpress
Project description:The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms of chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution, the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extra-telomeric sites contains interstitial telomeric sequences (or ITSs). However we also identified non-ITS sites, which are also satellite DNA but the ones mainly constitutive of centromeric and pericentromeric regions. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that, by binding to extratelomeric sequences, TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks.
2011-05-04 | GSE26005 | GEO
Project description:The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms of chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution, the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extra-telomeric sites contains interstitial telomeric sequences (or ITSs). However we also identified non-ITS sites, which are also satellite DNA but the ones mainly constitutive of centromeric and pericentromeric regions. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that, by binding to extratelomeric sequences, TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks. ChIP-SEQ experiment of transformed human fibroblast BJ cells with 3 antibodies (1 monoclonal anti-TRF1, 1 monoclonal anti-TRF2, 1 polyclonal anti-TRF2) and a negative control (proteinG without antibody used as the ChIP background)
2011-05-03 | E-GEOD-26005 | biostudies-arrayexpress
Project description:The mammalian telomere-binding protein Rap1 was found to have additional non-telomeric functions, acting as a transcriptional cofactor and a regulator of the NF-kB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo, and report on its unanticipated role in metabolic regulation and body weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function. In addition, using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, and at other interstitial loci. We have utilized microarrays to outline gene expression changes resulting from Rap1-deficiency when compared to the wild-type controls.
2013-06-01 | GSE46209 | GEO
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: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:The mammalian telomere-binding protein Rap1 was found to have additional non-telomeric functions, acting as a transcriptional cofactor and a regulator of the NF-kB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo, and report on its unanticipated role in metabolic regulation and body weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function. In addition, using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, and at other interstitial loci. We have utilized microarrays to outline gene expression changes resulting from Rap1-deficiency when compared to the wild-type controls. Total RNA was isolated from the liver and intra-abdominal white adipose tissue of 3 female Rap1 deficient mice and 3 control littermates at 6-8 weeks of age. Rap1 deficient mouse embryonic fibroblasts (MEF) were isolated from 13.5 day embryos, immortalized with SV40LgT, and stably infected with vector, Rap1-wildtype, or Rap1 carrying an isoleucine to arginine mutation at amino acid 312. Total RNA was extracted from MEFs following a similar protocol. The samples were labeled, hybridized, and scanned using standard protocols by the Core Facility at NYU Langone Medical Center on Affymetrix GeneChip Mouse Genome 430 2.0 Arrays.
2013-06-01 | E-GEOD-46209 | biostudies-arrayexpress
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 blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres in vivo, as shown among other approaches by ChIP-seq analysis, 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, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.
2023-10-23 | GSE196661 | GEO
Project description:RAP1 is one of the components of mammalian shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere protection has remained elusive. RAP1 binds along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres and its deficiency causes a premature aging in mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact in mouse survival, mice lacking both RAP1 and telomerase show a progressive decreased survival with increasing mouse generation as compared to telomerase single mutants. Telomere shortening was more pronounced in Rap1-/- Terc-/- than in Terc-/- counterparts, leading to an earlier onset of DNA damage and its consequent DNA damage response as well as accelerated degenerative pathologies in the intestines. In its turn, telomerase deficiency abolishes RAP1-mediated obesity and liver pathologies. Mouse embryonic fibroblasts with shorten telomeres present less amount of telomere-bound RAP1 but in contrast show higher numbers of RAP1 bound extratelomeric sites genomewide. Absence of RAP1 leads to deregulation of several metabolic pathways, and these changes were more pronounce in cells with short telomeres suggesting that RAP1 release from telomere foci could constitute a coordinated genomic response to telomere shortening. Our findings also demonstrate that although RAP1 is not a key factor in telomere capping under normal conditios, under stress situation such as critical telomere shortening RAP1 exerts an important function for telomere protection and justify its evolutionary conservation as a shelterin component in mammalian cells.
2016-11-16 | GSE79996 | GEO
Project description:RAP1 is well known as a telomere-binding protein; yet its functions in human stem cells remain unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by CRISPR/Cas9 and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 negatively regulated telomere length. In addition, RAP1 acted as a transcriptional regulator of RLEN by tuning the methylation status of its promoter region. Phenotypically, RAP1 deficiency resulted in enhanced self-renewal and delayed senescence in hMSCs rather than in hNSCs, suggesting a complex role of RAP1 in regulating lineage specific stem cell homeostasis. Altogether, these results indicate that RAP1 plays both telomeric and non-telomeric roles in regulating the homeostasis of human stem cells.
2018-11-20 | GSE122654 | GEO