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The epigenetic regulation of mammalian telomeres

Key Points

  • Telomeres are specialized chromatin structures located at the ends of chromosomes that protect chromosome ends from repair and degradation activities. Telomeres consist of G-rich repeats, which are bound by telomere-repeat-binding factors.

  • Telomerase is a cellular reverse transcriptase that synthesizes telomeric repeats de novo at chromosome ends. Recombination between telomeric sequences can also lead to telomere elongation independently of telomerase.

  • Telomeres and subtelomeres contain histone and DNA modifications that are also enriched at constitutive heterochromatin domains, such as those of pericentric heterochromatin.

  • From yeast to mammals, loss of heterochromatic marks at telomeres and subtelomeres results in telomere-length deregulation and disruption of telomeric silencing, or TPE (the transcriptional repression of genes located near the telomeres).

  • Loss of either histone methylation or DNA methylation at mammalian telomeres or subtelomeres also leads to de-repression of telomere recombination.

  • Histone- and DNA-methylation defects are associated with several human diseases, including cancer. These defects could have an impact on telomere-length regulation, and therefore contribute to disease phenotypes.

  • Telomere shortening to a critically short length leads to epigenetic defects at mammalian telomeres and subtelomeres, characterized by decreased histone and DNA methylation and increased histone acetylation.

  • Histone and DNA modifications provide a mechanism by which telomere repeats are counted and autoregulated.

  • Various diseases associated with ageing, including cancer and a number of premature ageing syndromes, are characterized by critically short telomeres, which in turn could affect the epigenetic status of telomeres and subtelomeres.

Abstract

Increasing evidence indicates that chromatin modifications are important regulators of mammalian telomeres. Telomeres provide well studied paradigms of heterochromatin formation in yeast and flies, and recent studies have shown that mammalian telomeres and subtelomeric regions are also enriched in epigenetic marks that are characteristic of heterochromatin. Furthermore, the abrogation of master epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlates with loss of telomere-length control, and telomere shortening to a critical length affects the epigenetic status of telomeres and subtelomeres. These links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomere-length defects.

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Figure 1: Structure of telomeres and subtelomeres in yeast and mammals.
Figure 2: Epigenetic modifications at mammalian pericentromeric and telomeric regions.
Figure 3: A model for the role of epigenetic modifications in telomere-length control.
Figure 4: Epigenetic defects at telomeres and human disease.

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Acknowledgements

I am indebted to E. Gilson (Ecole Normale Supérieure de Lyon, France) for useful discussions and critical reading of the manuscript. M.A.B.'s laboratory is funded by the Spanish Ministry of Education and Culture (MCyT), by the Regional Government of Madrid, the European Union and the Josef Steiner Cancer Research Award 2003.

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Glossary

Dyskeratosis congenita

A condition that is characterized by bone marrow failure, genetic instability, elevated cancer risk and other abnormalities. Mutations in telomerase components have been described in some cases.

Aplastic anaemia

A condition that results from a peripheral deficiency of all bone-marrow-derived haematopoietic lineages, such as red blood cells, platelets and leukocytes. There are many causes of this potentially fatal clinical syndrome. Mutations in telomerase components have been described in some cases.

Heterochromatin

Chromosomal material that is tightly coiled and generally inactive in terms of gene expression.

Nucleosome

The fundamental unit into which DNA and histones are packaged in eukaryotic cells. It is the basic structural subunit of chromatin and consists of 200 bp of DNA wrapped around an octamer of histone proteins.

Histone modifications

Histones undergo post-translational modifications that alter their interaction with DNA and nuclear proteins. In particular, the tails of histones H3 and H4 can be covalently modified at several residues. Modifications of the tail include methylation, acetylation, phosphorylation and ubiquitination, and affect several biological processes, including gene expression, DNA repair and chromosome condensation.

DNA methylation

DNA methylation occurs predominantly in repetitive genomic regions that contain CpG residues. DNA methylation represses transcription directly by inhibiting the binding of specific transcription factors, and indirectly by recruiting methyl-CpG-binding proteins and their associated repressive chromatin-remodelling activities.

PML body

Subnuclear compartments that are defined by the presence of the PML (promyelocytic leukaemia) protein. They have been associated with diverse nuclear functions including transcription, DNA repair, viral defense, stress, cell-cycle regulation, proteolysis and apoptosis.

Pericentric heterochromatin

The late-replicating, gene-sparse, transcriptionally inactive, condensed chromatin regions that are rich in repeated sequence and occur near the centromeres of chromosomes.

Small interfering RNA

A non-coding RNA (22 nucleotides long) that is derived from the processing of long dsRNA during RNAi. siRNAs direct the destruction or translation repression of mRNA targets that they hybridize with.

ICF

Immunodeficiency–centromeric instability–facial anomalies syndrome (ICF) is an extremely rare autosomal recessive disease that is characterized by profound immunodeficiency. Many ICF patients carry mutations of the DNMT3B gene, leading to DNA-methylation defects.

Rett syndrome

An X-linked dominant neurological disorder that mainly affects girls and is one of the most common causes of mental retardation in females. Typical Rett syndrome is due to a mutation in the MECP2 gene (methyl-CpG-binding protein 2) resulting in decreased DNA methylation.

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Blasco, M. The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8, 299–309 (2007). https://doi.org/10.1038/nrg2047

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