Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity

Koering, Catherine; Pollice, Alessandra; Zibella, Maria Pia; Bauwens, Serge; Puisieux, Alain; Brunori, Michèle; Brun, Catherine; Martins, L. Miguel; Sabatier, Laure; Pulitzer, John F.; Gilson, Éric

doi:10.1093/embo-reports/kvf215

Cited by 157 publications

(169 citation statements)

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“…In addition, they provide a connection between the transcriptional silencing of genes near the telomeres and the regulation of telomere length in mammalian cells 22,23 , in agreement with findings in yeast that show a role for histone H3 methyltransferases in telomere silencing 24 . The epigenetic regulation of telomere length may also have an impact in pathologies of cancer and aging.…”

supporting

confidence: 85%

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

et al. 2003

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Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins 1-3 . Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function 4-6 , but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) Suv39h1 and Suv39h2 (called SUV39DN mice). Suv39h1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions 7 . We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in diand trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by Suv39h1 and Suv39h2.The N-terminal tails of histones are subjected to post-translational modifications, including acetylation, methylation and phosphorylation, generating an extensive repertoire of chromatin structures 8,9 . Binding of factors that specifically recognize these modified histones mediate cellular responses 8,9 . Heterochromatic regions are enriched in methylated H3-Lys9, which creates a binding site for the chromobox proteins 9 , mediators of heterochromatin formation and epigenetic gene regulation. In D. melanogaster, HP1 is also required for telomere capping 4,5 . To investigate the impact of H3-Lys9 methylation on telomere length regulation and telomere function, we studied embryonic stem (ES) cells and mouse embryonic fibroblasts (MEFs) from SUV39DN mice 7 , which have less methylation of H3-Lys9 at the pericentric heterochromatin compared to wildtype mice 7 . First, we used terminal restriction fragment (TRF) analysis to estimate telomere length in these cells. Two independent SUV39DN ES cell cultures showed abnormally long telomeres, which were not present in wild-type ES cells (Fig. 1a). This finding was confirmed using MEFs (passage 1-2) derived from SUV39DN and wild-type littermate embryos (Fig. 1a). TRF analysis of increasing passages of the SUV39DN MEFs (D43) showed that the long telomeres in these MEFs were stable (Fig. 1b).Next, we carried out quantitative fluorescence in situ hybridization (Q-FISH) using a telomere-specific peptide nucleic acid probe. We determined the average telomere length for each ES-cell and ME...

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confidence: 85%

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

et al. 2003

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“…The euchromatic localization appears to contradict the heterochromatic nature of the telomere. On one hand, the epigenetic profile of telomeres is almost identical to that of pericentric heterochromatin (46) and there is evidence for a silencing telomere positioning effect, similar to that observed in budding yeast (47,48). On the other hand, when telomeres shorten, they acquire a more open (epigenetically active) state, probably to allow access to telomere elongation mechanisms (49).…”

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confidence: 53%

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

et al. 2008

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Telomeres are complex end structures that confer functional integrity and positional stability to human chromosomes. Despite their critical importance, there is no clear view on telomere organization in cycling human cells and their dynamic behavior throughout the cell cycle. We investigated spatiotemporal organization of telomeres in living human ECV-304 cells stably expressing telomere binding proteins TRF1 and TRF2 fused to mCitrine using four dimensional microscopy. We thereby made use of controlled light exposure microscopy (CLEM), a novel technology that strongly reduces photodamage by limiting excitation in parts of the image where full exposure is not needed. We found that telomeres share small territories where they dynamically associate. These territories are preferentially positioned at the interface of chromatin domains. TRF1 and TRF2 are abundantly present in these territories but not firmly bound. At the onset of mitosis, the bulk of TRF protein dissociates from telomere regions, territories disintegrate and individual telomeres become faintly visible. The combination of stable cell lines, CLEM and cytometry proved essential in providing novel insights in compartment-based nuclear organization and may serve as a model approach for investigating telomere-driven genome-instability and studying long-term nuclear dynamics. ' 2008 International Society for Advancement of Cytometry Key termstelomere; TRF1; TRF2; nuclear organization; chromatin dynamics; CLEM; live cell imaging TELOMERES are the natural ends of linear chromosomes. A mammalian telomere consists of a double stranded array of simple TTAGGG repeats ending in a single stranded overhang that folds back to form a T-loop structure (1). In combination with sufficient telomere repeats, a complex of indirect and direct telomere binding proteins, dubbed shelterin, assures proper telomere structure and function. The specificity of shelterin for telomeric DNA is due to the recognition of TTAGGG repeats by three of its components: the homodimers telomeric repeat binding factor 1 and 2 (TRF1 and TRF2) that bind the duplex part of telomeres, and protection of telomeres 1 that binds to the single stranded TTAGGG repeats present at the three-overhang and in the D loop of the T-loop configuration (2-5).The nucleus has a meticulous organization with functional relevance to the cell assuring proper gene expression, replication and genome stability (6-8). Telomeres are considered to play an important role in spatial genome organization. Whereas yeast telomeres are known to form few large silencing clusters at the heterochromatic nuclear periphery (9,10), there is no consensus on how telomeres are organized in the mammalian nucleus. From an architectural point of view, human telomeres have been proposed to be anchored to a nuclear scaffold, thereby possibly providing struc-

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“…We conclude that, whereas TRF2 inactivation is not alone sufficient for tumorigenic growth, it can generate changes involved in human cell transformation. The nature of these changes can be genetic, such as chromosome rearrangements provoked by end-to-end fusions, or epigenetic, such as altered telomere position effects (Baur et al, 2001;Koering et al, 2002). Of note, we found no evidence by M-FISH analysis of chromosome rearrangements shared by the clones having experienced TRF2 inactivation and leading to a high level of colony formation in soft agar.…”

Section: Discussionmentioning

confidence: 57%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to cradiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

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Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity

Cited by 157 publications

References 35 publications

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

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