Letter | Published:

Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres

Nature Genetics volume 39, pages 243250 (2007) | Download Citation

Subjects

Abstract

Mammalian telomeres have epigenetic marks of constitutive heterochromatin. Here, we study the impact of telomere length on the maintenance of heterochromatin domains at telomeres. Telomerase-deficient Terc−/− mice with short telomeres show decreased trimethylation of histone 3 at Lys9 (H3K9) and histone 4 at Lys20 (H4K20) in telomeric and subtelomeric chromatin as well as decreased CBX3 binding accompanied by increased H3 and H4 acetylation at these regions. Subtelomeric DNA methylation is also decreased in conjunction with telomere shortening in Terc−/− mice. In contrast, telomere repeat factors 1 and 2 show normal binding to telomeres independent of telomere length. These results indicate that loss of telomeric repeats leads to a change in the architecture of telomeric and subtelomeric chromatin consisting of loss of heterochromatic features leading to a more 'open' chromatin state. These observations highlight the importance of telomere repeats in the establishment of constitutive heterochromatin at mammalian telomeres and subtelomeres and point to histone modifications as important in counting telomere repeats.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611–622 (2005).

  2. 2.

    Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).

  3. 3.

    & New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21, 553–563 (2002).

  4. 4.

    & The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, R191–R196 (2005).

  5. 5.

    et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat. Cell Biol. 8, 416–424 (2006).

  6. 6.

    & The language of covalent histone modifications. Nature 403, 41–45 (2000).

  7. 7.

    et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

  8. 8.

    et al. A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

  9. 9.

    et al. Heterochromatin and tri-methylated lysine 20 of histone 4 in mammals. J. Cell Sci. 117, 2491–2501 (2004).

  10. 10.

    et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat. Cell Biol. 7, 420–428 (2005).

  11. 11.

    , , , & Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat. Genet. 36, 94–99 (2004).

  12. 12.

    , , & A role for the Rb family of proteins in controlling telomere length. Nat. Genet. 32, 415–419 (2002).

  13. 13.

    , , & Targeting of SIR1 protein establishes transcriptional silencing at HM loci and telomeres in yeast. Cell 75, 531–541 (1993).

  14. 14.

    et al. The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing. J. Cell Biol. 129, 909–924 (1995).

  15. 15.

    Mechanisms of silencing in Saccharomyces cerevisiae. Curr. Opin. Genet. Dev. 8, 233–239 (1998).

  16. 16.

    , , & Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117, 323–335 (2004).

  17. 17.

    , & Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2, 800–807 (2001).

  18. 18.

    , , & The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

  19. 19.

    et al. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat. Genet. 37, 1063–1071 (2005).

  20. 20.

    & DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat. Cell Biol. 7, 712 (2005).

  21. 21.

    , & Modification of subtelomeric DNA. Mol. Cell. Biol. 24, 4571–4580 (2004).

  22. 22.

    , , , & Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev. 17, 88–100 (2003).

  23. 23.

    , , & Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144, 589–601 (1999).

  24. 24.

    et al. Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA. Mol. Cell. Biol. 20, 4115–4127 (2000).

  25. 25.

    et al. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep. 3, 1055–1061 (2002).

  26. 26.

    , , & Telomere position effect in human cells. Science 292, 2075–2077 (2001).

  27. 27.

    et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

  28. 28.

    et al. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 21, 2207–2219 (2002).

  29. 29.

    et al. Strand-specific postreplicative processing of mammalian telomeres. Science 293, 2462–2465 (2001).

Download references

Acknowledgements

We are indebted to T. Jenuwein (Institute of Molecular Pathology, Vienna) for donation of the SUV39DN cells and to the CNIO Genomics and Epigenomics Unit for bisulfite sequencing experiments. TFL-Telo software was a gift from P. Lansdorp (The Terry Fox Laboratory). The plasmid containing 1.6 kb of TTAGGG repeats was a gift from T. de Lange (Rockefeller University). Rabbit polyclonal antibody to TRF2 was provided by E. Gilson (École normale Supérieure de Lyon). Research in the laboratory of M.A.B. is funded by the Spanish Ministry of Education and Science, the Regional Government of Madrid, the European Union and the Josef Steiner Cancer Award 2003.

Author information

Author notes

    • Roberta Benetti
    •  & Marta García-Cao

    These authors contributed equally to this work.

Affiliations

  1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain.

    • Roberta Benetti
    • , Marta García-Cao
    •  & María A Blasco

Authors

  1. Search for Roberta Benetti in:

  2. Search for Marta García-Cao in:

  3. Search for María A Blasco in:

Contributions

R.B. performed experiments for all manuscript figures except Supplementary Figure 1. M.G.C performed experiments for Figure 1, Figure 3 and Supplementary Figure 1.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to María A Blasco.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Telomere length in wild-type, G2 and G5 telomerase-null MEFs.

  2. 2.

    Supplementary Fig. 2

    Changes in H4K20:H4 ratio in telomeric chromatin in conjunction with telomere erosion.

  3. 3.

    Supplementary Table 1

    Primer sequences used for ChIP and bisulfite sequencing.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng1952

Further reading