Epigenetic Regulation of Telomere Length and Telomere Recombination

Disruptions of histone and DNA modifications at telomeres result in loss of telomere length control (Garcia-Cao et al. 2004, Gonzalo et al. 2005, Garcia-Cao et al. 2002) (Fig. 12.2). In particular, cells lacking the Suv39h1 and Suv39h2 HMTases show decreased trimethylated H3K9 at telomeres, which is concomitant with aberrant telomere elongation (Garcia-Cao et al. 2004). A similar deregulation of telomere length is seen cells that lack all three members of the retinoblastoma family and show decreased levels of H4K20 trimethylation at telomeres (Gonzalo et al. 2005, Garcia-Cao et al. 2002). All together, these findings suggest an important role of histone modifications in mammalian telomere length control (Fig. 12.2).

Independent of histone methylation, decreased DNA methylation at subtelomeric regions is also accompanied by dramatically elongated telomeres in the absence of loss in heterochromatic histone methylation marks (Gonzalo et al. 2006) (Fig. 12.2). Indeed, aberrantly elongated telomeres in DNMT-deficient cells show a further increase in H3K9me3 and H4K20me3 density, as well as in HP1 binding, suggesting that the length of telomere repeats controls the formation of heterochromatin domains at telomeres when heterochromatinizing activities (Suv39h and Suv420 HMTases) are present.

The demethylation of subtelomeric regions in the absence of DNMTs is also concomitant with increased homologous recombination between telomeric sequences, which is corrected by reintroduction of DNMT3a,3b into cells that lack these enzymes results (Gonzalo et al. 2006) (Fig.12.2). These results suggest that DNA methylation at subtelomeric repeats may regulate ALT, which relies on homologous recombination.

All together, these results suggest that DNA and histone methylation at telom-eric domains are an important mechanism for telomere length control. In turn, it has recently been shown that progressively shorter telomeres can also lead to epigenetic changes both in telomeric and subtelomeric chromatin (Benetti et al. 2007). In particular, short telomeres have a decreased density of heterochromatic histone marks such as H3K9me3 and H4K20me3 at telomeric repeats, as well as decreased binding of HP1. They are also characterized by an increased density of histone marks that are characteristic of more "open" or active chromatin domains, such as histone H3 and H4 acetylation (Benetti et al. 2007). In addition to these epigenetic changes at the TTAGGG repeats, subtelomeric regions show decreased histone methylation, increased histone acetylation, and a decrease in subtelomeric DNA methylation, suggesting that the length of the distal TTAGGG repeats influences the epigenetic status of subtelomeric chromatin (Benetti et al. 2007).

Of notice, similar to the findings described above for DNMT-deficient cells, the decreased DNA methylation seen at subtelomeric regions as a consequence of telomere shortening was also accompanied by increased telomere recombination (Benetti et al. 2007). This provides further support for a role of DNA methylation as a negative regulator of recombination at these regions, and might also provide an explanation for the fact that ALT is activated in the context of short telomeres in telomere-deficient cells and mice (Hande et al. 1999, Chang et al. 2003, Niida et al. 2000, Herrera et al. 2000).

The fact that short telomeres lead to a change in the epigenetic status of telomeric and subtelomeric chromatin may also explain the preferential elongation of short telomeres by telomerase. In particular, telomerase has been shown to specifically act on the shortest telomeres, both in budding yeast (Teixeira et al. 2004) and mammals (Samper et al. 2001, Hemann et al. 2001), raising the possibility that short telomeres have specific chromatin marks which are recognized by the telom-erase complex. The precise nature of these marks is still unknown but may include increased H3 and H4 actelylation, as this mark is increased associated to telomere loss (Benetti et al. 2007).

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