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

Nature Genetics volume 36, pages 94–99 (2004)Cite this article

Abstract

Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins1,2,3. Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function4,5,6, 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 regions7. 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 di- and 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.

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Figure 1: Telomere length determination in SUV39DN MEF and ES cells.
Figure 2: Identification of chromosomes harboring very long telomeres in SUV39DN cells.
Figure 3: Loss of heterochromatin features at SUV39DN telomeres.
Figure 4: Model for epigenetic regulation of telomere length.

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Acknowledgements

We thank S. Gonzalo and M. Serrano for critical reading of the manuscript and discussions and A.A.H.A. Derijck for generating SUV39DN ES cells. M.G.-C. is a predoctoral fellow from the Spanish Ministry of Science and Technology. A.H.F.M.P. is the recipient of a Marie Curie fellowship. Research in the laboratory of T.J. is supported by the Institute of Molecular Pathology through Boehringer Ingelheim and by grants from the Vienna Economy Promotion Fund, the European Union and the GEN-AU initiative, which is financed by the Austrian Ministry of Education, Science and Culture. Research at the laboratory of M.A.B. is funded by grants from the Spanish Ministry of Science and Technology, the Regional Government of Madrid and the European Union and by the Department of Immunology and Oncology.

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Authors and Affiliations

  1. Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, E-28029, Spain

    Marta García-Cao & María A Blasco

  2. Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, A-1030, Austria

    Roderick O'Sullivan, Antoine H F M Peters & Thomas Jenuwein

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  1. Marta García-Cao
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  2. Roderick O'Sullivan
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  3. Antoine H F M Peters
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  5. María A Blasco
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Correspondence to María A Blasco.

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García-Cao, M., O'Sullivan, R., Peters, A. et al. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36, 94–99 (2004). https://doi.org/10.1038/ng1278

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