A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs

Abstract

Protection of chromosome ends from DNA repair and degradation activities is mediated by specialized protein complexes bound to telomere repeats. Recently, it has become apparent that epigenetic regulation of the telomeric chromatin template critically impacts on telomere function and telomere-length homeostasis from yeast to man. Across all species, telomeric repeats as well as the adjacent subtelomeric regions carry features of repressive chromatin. Disruption of this silent chromatin environment results in loss of telomere-length control and increased telomere recombination. In turn, progressive telomere loss reduces chromatin compaction at telomeric and subtelomeric domains. The recent discoveries of telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming, further highlights a central role of telomere chromatin changes in ontogenesis. In addition, telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of telomere length and telomere chromatin. In this review, we will discuss the epigenetic regulation of telomeres across species, with special emphasis on mammalian telomeres. We will also discuss the links between epigenetic alterations at mammalian telomeres and telomere-associated diseases.

Figure 1

Assembly of mammalian telomeric and subtelomeric heterochromatin. Scheme showing a model for the assembly of telomeric and subtelomeric heterochromatin. Suv39 h1 and h2 HMTases tri-methylate H3K9, which in turn generates a high-affinity site for HP1. HP1 can recruit Suv4-20 h1 and h2 HMTases to telomeres and subtelomeres, thereby tri-methylating H4K20 at these regions. The Rb family proteins (Rb1, Rbl1, and Rbl2) can directly interact with Suv420 HMTases and with HP1, thus influencing the levels of H4K20m3. Dicer is essential for the maturation of miRNAs including the miR290 cluster. miR290 cluster expression in ES cells results in post-transcriptional repression of Rbl2 (p130), a transcriptional repressor of mammalian DNA methyltransferases (DNMTs). Low Rbl2 levels ensure the establishment of global and subtelomeric DNA methylation patterns in ES cells. A lack of mature miRNA290 cluster results in repression of DNMTs by uncontrolled expression of Rbl2. Consequently, a global decrease in DNA methylation unleashes recombination leading to telomere elongation and increased chromatin compaction at telomeric and subtelomeric repeats mediated by Suv39h and Suv4-20h HMTases. Loss of heterochromatin in cells lacking Dicer, DNMTs, Suv39h, or Suv4-20h HMTases results in increased telomeric recombination and telomere elongation.

Figure 2

TERRA/TelRNAs associate to telomeric chromatin and may be involved in regulation of telomere length. Model for a role of telomeric RNAs in the regulation of telomere length. TERRA/TelRNA acts as a potent inhibitor of telomerase activity in vitro, possibly by formation of RNA:RNA hybrids with the template region of the telomerase RNA component.

Figure 3

Reprogramming of telomeres upon induction of plutipotency in differentiated cells. Telomeres in primary MEFs are shorter than in ES cells and are organized into a highly compact chromatin structure with low TelRNA/TERRA expression. Induction of pluripotency by retroviral transduction of Oct4, Sox2, Kfl4, (c-myc), results in nuclear reprogramming and the generation of pluripotent iPS cells, which are functionally equivalent to ES cells. Reprogramming results in a dramatic upregulation of telomerase activity concomitant with a reduction of H3K9me3, H4K20me3, HP1, and DNA methylation at telomeres and subtelomeres as well as an increase in TelRNA/TERRA expression. Telomerase efficiently elongates telomeres until the natural limit of telomere length of pluripotent mouse ES cells has been reached.