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

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.