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. Epigenetic modifications are key players in the regulation of fly and yeast telomeres, and recent studies indicate that the same applies in mammalian cells. These findings have implications for our understanding of the roles of telomeres in ageing and cancer. 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 methyltransfe