Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II

Nature Cell Biology volume 10, pages 228–236 (2008)Cite this article

Abstract

Mammalian telomeres consist of non-coding TTAGGG repeats that are bound by the multi-protein complex 'shelterin', thus protecting chromosome ends from DNA repair mechanisms and degradation1. Mammalian telomeric chromatin is enriched for the constitutive heterochromatin marks H3K9me3, H4K20me3 and HP1 (refs 2–7). Similar to pericentric heterochromatin, telomeric heterochromatin is thought to be fundamental for the maintenance of chromosomal integrity8. Here, we report that telomeric repeats are transcribed by DNA-dependent RNA polymerase II, which, in turn, interacts with the TRF1 shelterin protein. Telomeric RNAs (TelRNAs) contain UUAGGG repeats, are polyadenylated and are transcribed from the telomeric C-rich strand. Transcription of mammalian telomeres is regulated by several mechanisms, including developmental status, telomere length, cellular stress, tumour stage and chromatin structure. Using RNA-flourescent in situ hybridization (FISH), we show that TelRNAs are novel structural components of telomeric chromatin. Importantly, we provide evidence that TelRNAs block the activity of telomerase in vitro, suggesting that TelRNAs may regulate telomerase activity at chromosome ends. Our results indicate that TelRNAs are novel components of mammalian telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related diseases, such as cancer and ageing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Transcription of [UUAGGG]n repeat containing RNAs from mammalian telomeres is developmentally regulated and restricted to the nucleus.
Figure 2: TelRNAs are polyadenylated RNA Pol II transcripts.
Figure 3: TelRNAs are associated with telomeric DNA repeats, upregulated on heat shock and massively accumulated when expressed close to the inactive X chromosome.
Figure 4: Epigenetic status of mammalian telomeres influences telomeric transcription.
Figure 5: r(UUAGGG)3 RNA oligonucleotides block telomerase activity in vitro and are downregulated in advanced human cancer stages.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Garcia-Cao, M., Gonzalo, S., Dean, D. & Blasco, M. A. A role for the Rb family of proteins in controlling telomere length. Nature Genet. 32, 415–419 (2002).

    Article  CAS  Google Scholar 

  5. Garcia-Cao, M., O'Sullivan, R., Peters, A. H., Jenuwein, T. & Blasco, M. A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nature Genet. 36, 94–99 (2004).

    Article  CAS  Google Scholar 

  6. Benetti, R., Garcia-Cao, M. & Blasco, M. A. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nature Genet. 39, 243–250 (2007).

    Article  CAS  Google Scholar 

  7. Benetti, R. et al. Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination. J. Cell Biol. 178, 925–936 (2007).

    Article  CAS  Google Scholar 

  8. Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nature Rev. Genet. 8, 299–309 (2007).

    Article  CAS  Google Scholar 

  9. Gottschling, D. E., Aparicio, O. M., Billington, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990).

    Article  CAS  Google Scholar 

  10. Levis, R., Hazelrigg, T. & Rubin, G. M. Effects of genomic position on the expression of transduced copies of the white gene of Drosophila. Science 229, 558–561 (1985).

    Article  CAS  Google Scholar 

  11. Nimmo, E. R., Cranston, G. & Allshire, R. C. Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes. EMBO J. 13, 3801–3811 (1994).

    Article  CAS  Google Scholar 

  12. Baur, J. A, Zou, Y., Shay, J. W. & Wright, W. E. Telomere position effect in human cells. Science 292, 2075–2077 (2001)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Bernstein, E. & Allis, C. D. RNA meets chromatin. Genes Dev. 19, 1635–1655 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Mattick, J. S. & Makunin, I. V. Non-coding RNA. Hum. Mol. Genet. 15, R17–R29 (2006).

    Article  CAS  Google Scholar 

  17. Valgardsdottir, R. et al. Structural and functional characterization of noncoding repetitive RNAs transcribed in stressed human cells. Mol. Biol. Cell 16, 2597–2604 (2005).

    Article  CAS  Google Scholar 

  18. Rizzi, N. et al. Transcriptional activation of a constitutive heterochromatic domain of the human genome in response to heat shock. Mol. Biol. Cell 15, 543–551 (2004).

    Article  CAS  Google Scholar 

  19. Jolly, C. et al. Stress-induced transcription of satellite III repeats. J. Cell Biol. 164, 25–33 (2004).

    Article  CAS  Google Scholar 

  20. Masui, O. & Heard, E. RNA and protein actors in X-chromosome inactivation. Cold Spring Harb. Symp. Quant. Biol. 71, 419–428 (2006).

    Article  CAS  Google Scholar 

  21. Franke, A. & Baker, B. S. The rox1 and rox2 RNAs are essential components of the compensasome, which mediates dosage compensation in Drosophila. Mol. Cell 4, 117–122 (1999).

    Article  CAS  Google Scholar 

  22. Kelley, R. L. et al. Epigenetic spreading of the Drosophila dosage compensation complex from roX RNA genes into flanking chromatin. Cell 98, 513–522 (1999).

    Article  CAS  Google Scholar 

  23. Cohen, H. R. & Panning, B. XIST RNA exhibits nuclear retention and exhibits reduced association with the export factor TAP/NXF1. Chromosoma 116, 373–383 (2007).

    Article  CAS  Google Scholar 

  24. Chan, S. W. & Blackburn, E. H. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21, 553–563 (2002).

    Article  CAS  Google Scholar 

  25. Teixeira, M. T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase-extendible and-nonextendible states. Cell 117, 323–335 (2004).

    Article  CAS  Google Scholar 

  26. Ancelin, K. et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol. Cell Biol. 22, 3474–3487 (2002).

    Article  CAS  Google Scholar 

  27. Azzalin, C. M., Reichenbach, P., Khoriauli, L., Giulotto, E. & Lingner, J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318, 798–801 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Murchison, E. P., Partridge, J. F., Tam, O. H., Cheloufi, S. & Hannon, G. J. Characterization of Dicer-deficient murine embryonic stem cells. Proc. Natl Acad. Sci. USA 102, 12135–12140 (2005).

    Article  CAS  Google Scholar 

  30. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  Google Scholar 

  31. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  Google Scholar 

  32. Wutz, A. & Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell 5, 695–705 (2000).

    Article  CAS  Google Scholar 

  33. Benetti, R. et al. The death substrate Gas2 binds m-calpain and increases susceptibility to p53-dependent apoptosis. EMBO J. 20, 2702–2714 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to T. Jenuwein for the Suv39h and Suv4-20 cells and to G. Hannon for the Dicer-null cells. We thank M. L. Cayuela for Danio rerio RNA. Thanks to R. Benetti, P. Klatt and A. Canela for helpful discussions and help with the preparation of the manuscript and to R. Serrano for mouse care and genotyping. S.S. is a postdoctoral fellow funded by EMBO. M.A.B's laboratory is funded by the Spanish Ministry of Education and Culture (SAF2001-1869, GEN2001-4856-C13-08), by the Regional Government of Madrid (08.1/0054/01), the European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842, MOL CANCER MED LSHC-CT-2004-502943) and the Josef Steiner Award 2003.

Author information

Authors and Affiliations

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

    Stefan Schoeftner & Maria A. Blasco

Authors
  1. Stefan Schoeftner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria A. Blasco
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S. and M.A.B designed the experiments and S.S. carried out the experiments.

Corresponding author

Correspondence to Maria A. Blasco.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3, S4 and S5 (PDF 740 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schoeftner, S., Blasco, M. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10, 228–236 (2008). https://doi.org/10.1038/ncb1685

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1685

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing