Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness

Abstract

Telomeres comprise specialized nucleic acid-protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length-dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat-binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from induced pluripotent stem cells having long telomeres, and differentiated cells obtained from human embryonic stem cells with relatively long telomeres have a longer lifespan. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the nonlocal influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.

Keywords: chromosome end; de-differentiation; extra-telomeric function; gene regulation; genome organization; neurodegenerative disease; pluripotency; shelterin; stem cells; telomere.

Figure 1.

TPE-OLD. Physical association of relatively long telomeres by looping to the subtelomeric regions results in transcriptional repression of genes located in the subtelomeres. In relatively short telomeres, the looping is lost, and genes become transcriptionally active.

Figure 2.

TSP. The model implies partitioning of TRF2 between telomeric and extra-telomeric sites. Longer telomeres sequester more TRF2, thereby depleting TRF2 binding at extra-telomeric sites. Conversely, when telomeres shorten, an increase in TRF2 binding at promoters influences TRF2-mediated chromatin modifications and transcription.

Figure 3.

Extra-telomeric functions of shelterin proteins independent of telomeres. Examples of noncanonical function(s) of shelterin proteins are shown. Extra-telomeric binding of TRF2 to G-quadruplex–forming sequences across the genome induces epigenetic and transcriptional changes. NF-κB signaling is modulated through the shelterin factor RAP1: telomere-independent interaction of RAP1 with the IKK complex results in phosphorylation of the NF-κB p65 subunit, leading to activation of NF-κB target gene(s). Mitochondrial localization of TIN2, another shelterin protein, was reported to negatively regulate oxidative phosphorylation.

Figure 4.

Role of telomeres in stem cell homeostasis. Importance of telomere length in maintaining stemness. Stem cells with relatively long telomeres are reported to retain stemness, whereas reduction of telomere length is generally observed during differentiation and/or in differentiated cells.