Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

Summary Proper telomerelength is essential for embryonic stem cell(ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotentstate similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomereextension in these cells. However, the mechanism by which Zscan4 extends telomeresremains elusive. Here, we show that Zscan4 facilitates telomereelongation by inducing global DNA demethylationthrough downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1and promotes their degradation, which depends on the E3 ubiquitin ligaseactivity of Uhrf1. Blocking DNA demethylationprevents telomereelongation associated with Zscan4 expression, suggesting that DNA demethylationmediates the effect of Zscan4. Our results define a molecular pathwaythat contributes to the maintenance of telomerelength homeostasis in mESCs.