Analysis of telomere lengths in cloned sheep

Shiels, Paul G.; Kind, Alexander; Campbell, Keith; Waddington, David; Wilmut, Ian; Colman, Alan; Schnieke, Angelika

doi:10.1038/20580

Cited by 316 publications

(147 citation statements)

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“…Finally, our findings imply that epigenetic errors could alter telomere length in mammals and help explain the differential resetting of telomere length in different cloned animals 20,21 . 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 .…”

mentioning

confidence: 67%

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: 67%

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

et al. 2003

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“…Another measure of reprogramming of somatic nuclei is the potential to restore the telomere size and to overcome senescence [65][66][67][68] . Although there is some evidence that telomere length is restored in somatic nuclei after transplantation into oocytes, most DNA mutations in the somatic nucleus cannot be repaired.…”

Section: Reprogramming Somatic Nuclei In the Oocytementioning

confidence: 99%

Reprogramming of genome function through epigenetic inheritance

Surani

2001

Nature

409

296

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Most cells contain the same set of genes and yet they are extremely diverse in appearance and functions. It is the selective expression and repression of genes that determines the specific properties of individual cells. Nevertheless, even when fully differentiated, any cell can potentially be reprogrammed back to totipotency, which in turn results in re-differentiation of the full repertoire of adult cells from a single original cell of any kind. Mechanisms that regulate this exceptional genomic plasticity and the state of totipotency are being unravelled, and will enhance our ability to manipulate stem cells for therapeutic purposes.

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“…Telomeres of Dolly, the cloned sheep, which was derived from an adult mammary epithelial cell, were shorter when compared with age-matched, naturally bred counterparts and correlated with telomere length of the donor cells (Shiels et al 1999). Subsequently, however, the vast majority of cloning studies reported that telomere length in cloned cattle, pigs, goats and mice are comparable with age-matched, naturally bred controls even when senescent donor cells were used for cloning (Jiang et al 2004, Betts et al 2005, Jeon et al 2005, Schaetzlein & Rudolph 2005.…”

Section: Telomere Length and Somatic Cloningmentioning

confidence: 99%

Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning

Niemann¹,

Tian²,

King³

et al. 2008

Reproduction

195

116

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The birth of 'Dolly', the first mammal cloned from an adult donor cell, has sparked a flurry of research activities to improve cloning technology and to understand the underlying mechanism of epigenetic reprogramming of the transferred somatic cell nucleus. Especially in ruminants, somatic cell nuclear transfer (SCNT) is frequently associated with pathological changes in the foetal and placental phenotype and has significant consequences for development both before and after birth. The most critical factor is epigenetic reprogramming of the transferred somatic cell nucleus from its differentiated status into the totipotent state of the early embryo. This involves an erasure of the gene expression program of the respective donor cell and the establishment of the well-orchestrated sequence of expression of an estimated number of 10 000-12 000 genes regulating embryonic and foetal development. The following article reviews the present knowledge on the epigenetic reprogramming of the transferred somatic cell nucleus, with emphasis on DNA methylation, imprinting, X-chromosome inactivation and telomere length restoration in bovine development. Additionally, we briefly discuss other approaches towards epigenetic nuclear reprogramming, including the fusion of somatic and embryonic stem cells and the overexpression of genes crucial in the formation and maintenance of the pluripotent status. Improvements in our understanding of this dramatic epigenetic reprogramming event will be instrumental in realising the great potential of SCNT for basic biological research and for various agricultural and biomedical applications.

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Analysis of telomere lengths in cloned sheep

Cited by 316 publications

References 9 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

Reprogramming of genome function through epigenetic inheritance

Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning

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