Polyadenylated Telomeric Noncoding RNA Functions as a Pivotal Therapeutic Target of Anti-Ageing to Stabilize Telomere Length of Chromosomes Via Collaborating With Zscan4c.

Xiaojuan Xu,Zhengju Chen,Xiaohe Tian,Wei Wu

doi:10.3389/fphar.2021.822779

Abstract

Telomeres are closely associated with the development of cell aging. Shortening or erosion of telomeres will cause cell mortality, suggesting that the maintenance of telomere integrity facilitates cell anti-senescence. However, the mechanism of how to keep the telomere length remains fragmentary. Here, we found that polyadenylated telomeric noncoding RNA (TERRA) can promote the self-renewal when overexpressed in mouse embryonic stem cells (mESCs), implying that TERRA with polyadenylation is critical for mESC maintenance. Further studies revealed that TERRA with a polyadenylated tail plays an important role in the sustenance of telomere length. High-throughput sequencing and quantitative real-time PCR show that zinc finger and SCAN domain containing 4C (Zscan4c) may be a potential target of TERRA. Zscan4c is negatively regulated by TERRA and collaborates with TERRA to stabilize the telomere length of chromosomes in mESCs. Our study not only identifies TERRA as a potential novel factor of telomere length regulation and uncovers the new molecular mechanism of cell anti-aging, but also indicates that Zscan4c could be a key therapeutic target candidate for therapy in dysfunctional chromosome diseases. These data will expand our understanding of the cell fate regulatory network and will be beneficial to drug discovery and theragnostics for antiaging and anticancer therapy in the future.

Highlights

Aging, a progressive physiological degeneration, is a risk factor for many age-related diseases, even cancer (Lopez-Otin et al, 2013)
For mouse embryonic stem cells (mESCs) stemness can be maintained under serum/LIF medium or serum-free medium N2B27/2i conditions [2i contains the two small molecule inhibitors CHIR99021 (CHIR) and PD0325901 (PD03)], the pLKO.1-telomeric noncoding RNA (TERRA) and PB-TERRA cells were cultured under these conditions
TERRA without polyadenylation is not sufficient to be a substitute for other factors to maintain mESCs

Summary

Introduction

A progressive physiological degeneration, is a risk factor for many age-related diseases, even cancer (Lopez-Otin et al, 2013). Studies on anti-aging therapies are usually performed at the molecular, cellular, and organismal level. Accumulating evidence indicates that preventing cellular senescence strongly contributes to organismal anti-aging and anti-cancer (Chen et al, 2020; Khosla et al, 2020). CAGAAGCCTGGCATTCCCT a prominent phenomenon underlying the senescence process at the molecular level is the shortening of telomeres inside the cell nucleus (Chakravarti et al, 2021). Telomeres are specialized structures containing tandem short G-rich repeats at the ends of linear chromosomes that ensure chromosomes stabilization. They have an inherent ability to prevent end-to-end fusions and inappropriate DNA damage response. Telomere length is likely altered by a variety of factors; the mechanism by which telomere length is regulated remains fragmentary

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