Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells.

Jiameng Dan,Lin Liu,Zhongcheng Zhou,David L. Keefe,Hua Wang,Renpeng Guo,Fang Wang

doi:10.3390/cells11030456

Abstract

Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the underlying mechanisms ensuring the telomere length maintenance are unclear. Here, using late generation telomerase KO (G4 Terc-/-) ESCs as a model, we show that Zscan4, highly upregulated in G4 Terc-/- ESCs, is responsible for the prolonged culture of these cells with stably short telomeres. Mechanistically, G4 Terc-/- ESCs showed reduced levels of DNA methylation and H3K9me3 at Zscan4 promoter and subtelomeres, which relieved the expression of Zscan4. Similarly, human ZSCAN4 was also derepressed by reduced H3K9me3 at its promoter in ALT U2 OS cells, and depletion of ZSCAN4 significantly shortened telomeres. Our results define a similar conserved pathway contributing to the telomere maintenance in telomerase-deficient late generation mESCs and human ALT U2OS cancer cells.

Highlights

The late generation telomerasedeficient mouse embryonic stem (ES) cells and telomerase-deficient human alternative lengthening of telomeres (ALT) cancer cells are able to propagate for numerous passages [7,41,42]
We propose that Zscan4, which is highly upregulated in those telomerasedeficient late generation mouse ES cells and human ALT U2 OS cells, contributes to telomere maintenance of those cells without telomerase activities
We show that telomere lengths of late generation G4 Terc-/- ES cells maintain stable levels while telomeres of WT ES cells lengthen remarkably during prolonged passaging

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mammalian telomeres consist of repetitive G-rich sequences and associated proteins at the ends of linear chromosomes and function in the maintenance of chromosomal stability and integrity [1,2]. Telomeres are primarily maintained by active telomerase which is composed of telomerase reverse transcriptase (TERT), telomerase RNA (TERC), and dyskerin [2]. Telomerase is expressed highly in a subset of stem cells, as well as in most immortal and cancer cells, presumably to support their indefinite proliferation and selfrenewal [3,4]. Most mammalian somatic cell types do not express telomerase activity, such that telomeres shorten progressively with each cell cycle and the end replication problem ensues [5,6]

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Results

Conclusion