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Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres

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.

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Figure 1: Histone changes at the telomeric chromatin associated to telomere erosion.
Figure 2: Increased histone acetylation at pericentric heterochromatin in Suv39DN cells.
Figure 3: Histone marks at pericentric heterochromatin in cells with progressively shorter telomeres.
Figure 4: Loss of subtelomeric heterochromatic features in telomerase-deficient mice with short telomeres.
Figure 5: Loss of subtelomeric DNA methylation in telomerase-deficient mice with short telomeres.
Figure 6: Increased telomeric sister chromatid exchange and APBs in late-generation telomerase-deficient cells.

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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.

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Authors

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.

Corresponding author

Correspondence to María A Blasco.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Telomere length in wild-type, G2 and G5 telomerase-null MEFs. (PDF 1323 kb)

Supplementary Fig. 2

Changes in H4K20:H4 ratio in telomeric chromatin in conjunction with telomere erosion. (PDF 96 kb)

Supplementary Table 1

Primer sequences used for ChIP and bisulfite sequencing. (PDF 63 kb)

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Benetti, R., García-Cao, M. & Blasco, M. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet 39, 243–250 (2007). https://doi.org/10.1038/ng1952

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