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, noncoding 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.

Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo

“…This suggestion is supported by the significantly shortened telomeres observed in the granulosa cell compartment of ArKO mice ( Fig. 2 and 4), as telomere deregulation underpins cell proliferative lifespan (Harrington and Robinson, 2002;Blasco, 2007;Schoeftner and Blasco, 2009). Consistently, late-generation female telomerase-negative mTR −/− mice, which lack the RNA template for telomerase, are infertile and have smaller ovaries than their wild-type counterparts (Lee et al, 1998).…”

TERRA transcripts are bound by a complex array of RNA-binding proteins

“…Several biological processes as well as cellular stresses have been described to infl uence TERRA levels and their nuclear localization and accumulation including the telomeric chromatin stage, telomere length, heat shock, exogenously infl icted DNA damage, as well as ontogenesis and cancer 6,8,32 (reviewed in Schoeft ner and Blasco 9 ). However, the TERRA-bound factors controlling all of these processes remain largely unknown.…”

“…TERRA levels are modulated by a number of factors, including telomeric chromatin status, cellular stresses, as well as during ontogenesis and cancer 6 . More recently, TERRA abundance was shown to be tightly regulated during nuclear reprogramming of diff erentiated cells into induced pluripotent stem cells, highlighting the importance of TERRA regulation during the acquisition of a pluripotent state (Marion et al 8 ; reviewed in Schoeft ner and Blasco 9 ). Until recently, however, the trans -acting factors (for example, RNAbinding proteins (RBPs), miRNAs, and so on) and the mechanisms controlling TERRA levels remained unaddressed.…”

Oligonucleotide Models of Telomeric DNA and RNA Form a Hybrid G-quadruplex Structure as a Potential Component of Telomeres

“…These findings raise the important question of how telomeric RNA is specifically associated with telomeric DNA in terms of chromosome end protection. The existence of telomeric RNA may reveal a new level of protection of chromosome ends that could provide new insights into fundamental biological processes such as cancer and aging (11)(12)(13)(14). Determining the structure and function of TERRA RNA will be essential for understanding telomere biology and telomere-related diseases.…”