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Molecular basis of TPE-OLD [RNA-seq]

ABSTRACT: Among epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomeric-dependent long-distance loops, with a reach of 10Mb from the telomeres. However, TPE-OLD remain poorly defined. We used cells with controlled telomere length combined to a genome wide approach revealing its transcriptome and methylome. We identified a common cis element that behaved as an insulator/ enhancer. By using reporter assays integrating this element, we disclosed additional trans partners further validated by in silico data. Exploiting our cellular model we observed the depletion of one candidate (RBPJ) at TPE-OLD associated loci concomitant to telomere shortening. Therefore, we conclude that TPE-OLD is orchestrated by Alu-like elements acting as enhancers in association with RBPJ. We propose that TPE-OLD functions by the coordinated action of newly evolved enhancers; an associated protein RBPJ and telomere length to produce an adapted response to external stimuli (i.e., Aging)

ORGANISM(S): Homo sapiens

PROVIDER: GSE213281 | GEO | 2023/01/05

REPOSITORIES: GEO

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Molecular basis of TPE-OLD [methylation]

Project description:Among epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomeric-dependent long-distance loops, with a reach of 10Mb from the telomeres. However, TPE-OLD remain poorly defined. We used cells with controlled telomere length combined to a genome wide approach revealing its transcriptome and methylome. We identified a common cis element that behaved as an insulator/ enhancer. By using reporter assays integrating this element, we disclosed additional trans partners further validated by in silico data. Exploiting our cellular model we observed the depletion of one candidate (RBPJ) at TPE-OLD associated loci concomitant to telomere shortening. Therefore, we conclude that TPE-OLD is orchestrated by Alu-like elements acting as enhancers in association with RBPJ. We propose that TPE-OLD functions by the coordinated action of newly evolved enhancers; an associated protein RBPJ and telomere length to produce an adapted response to external stimuli (i.e., Aging)

2023-01-05 | GSE213427 | GEO

Telomere length effect on genes near the telomere in myoblasts

Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed. Compare expression of genes within 10MB of the telomere in normal myoblasts with long (15 kb) and short (6 kb) telomeres.

2014-07-17 | E-GEOD-48973 | biostudies-arrayexpress

RNA-Seq of young and senescent cells with empty vector, TRF2 overexpression or LMNB1 downregulation

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

Endogenous genes regulated by telomere length

Project description:Reporter genes inserted immediately adjacent to telomeres are frequently repressed in cells of model organisms as well as human cells, a phenomena referred to as telomere position effect (TPE). TPE has been proposed to be involved in regulation of cellular senescence, cancer and aging. However, the identification of endogenous genes in human cells regulated by natural telomeres has not been reported. Here we show that the expression of interferon simulated gene 15 (ISG15, located on 1p36.33, G1P2) varies with telomere length. ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases with the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The up-regulation of ISG15 is independent of p53 and type I interferon, and is not due to replicative senescence and DNA damage. In human skin specimens obtained from various aged individuals, ISG15 was up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and it suggests that telomeres may be involved in the regulation of human physiology that contributes to the process of aging. Keywords: cell type comparison

2007-12-07 | GSE6799 | GEO

Mouse spleen LC-MSMS: effects of age and immune challenge

Project description:Ageing is characterized by the progressive lowering of the acute innate immune response and the progressive up-regulation of low-grade inflammation (i.e. inflammaging). At the cellular level, telomeres are considered as a mark of ageing as their length is progressively shortened. However, the links between telomeres and innate immune ageing remain undefined. Using a proteomic approach conducted on laboratory mice, we tested whether the experimental triggering of an acute innate response is deleterious for telomere maintenance, and whether this is dependent of age. To do so, we challenged young and old mice using bacterial lipopolysaccharide (LPS) and measured individuals’ end-points of telomere length and proteomic profiles in spleen tissue.

2019-03-12 | PXD009005 | Pride

Mammalian telomeres reforged with non-telomeric sequences

Project description:Telomere is a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes, but in some species or telomerase-defective situations, alternative telomere lengthening (ALT) mechanism is utilized to protect chromosomal ends. Telomere loss can induce telomere recombination by which specific sequences can be recruited into telomeres. However, canonical telomeric repeat-based telomeres have been found in mammals. Here, we show that mammalian telomeres can also be completely reconstituted using a non-telomeric unique sequence. We found that a specific subtelomeric element, named as mouse template for ALT (mTALT), is utilized for repairing telomeric DNA damage and composing new telomeric sequences in mouse embryonic stem cells. We found a high-level of non-coding mTALT transcript despite the heterochromatic nature of mTALT-based telomere. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributed to maintaining telomere stability by regulating telomeric transcriptions. Our findings reveal novel molecular features of potential telomeric sequences which can reconstitute telomeres during cancer formation and evolution.

2020-07-17 | MSV000085772 | MassIVE

Telomere length effect on genes near the telomere in myoblasts

2014-07-17 | GSE48973 | GEO

Telomerase is essential for cardiac differentiation and sustained metabolism of human cardiomyocytes

Project description:The scRNA seq was performed on day 12 of hiPSC-cardiomyocyte differentiation protocol with 3 different conditions of telomere length at the hiPSC stage, namely- long telomeres, intermediate telomeres and short telomeres. The analysis showed expected clusters of the mesodermal lineage but a shift of clusters was observed depending upon the telomere legth status of the parent CRISPRi TERT hiPSCs used for differentiation

2024-04-25 | GSE239887 | GEO

Mutational analysis of Rap1 reveals specific vulnerability for long telomeres fusions

Project description:The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length homeostasis. Previous studies addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a genetic screen in combination with high throughput sequencing to identify several amino acid positions in Rap1 that have a key role in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner with longer telomeres being prone to undergoing end fusions, while short telomeres are sufficiently protected. The protection of long telomeres requires their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrates that longer telomeres pose an additional challenge for the maintenance of genome integrity and provides an explanation for a species-specific upper limit in telomere length.

2022-08-10 | GSE190759 | GEO

Telomere dysfunction and fusion during the progression of chronic lymphocytic leukaemia: evidence for a telomere crisis

Project description:We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. Array CGH was undertaken on six individuals (five CLL stage C and one stage A) that displayed evidence of telomere dysfunction, and four (three CLL stage A and one stage B) that displayed longer and apparently stable telomeres.

2010-05-28 | E-GEOD-22016 | biostudies-arrayexpress

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