The exit of naïve pluripotency contains a metabolism-induced checkpoint for telomere homeostasis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
During peri-implantation development, the pluripotent tissue of the early embryo undergoes profound cellular and biochemical reprogramming. These transformations are essential for subsequent development, yet how they are coordinated with the preservation of genome integrity remains poorly understood. Here, we uncover a telomere length checkpoint that is elicited by metabolic remodeling as mouse embryonic stem cells (ESCs) transition from the naïve to formative pluripotent state. We show that the exit of naïve pluripotency is marked by accelerated mitochondrial respiration and de novo lipogenesis, fueling lipid droplet accumulation required for tissue remodeling. Unexpectedly, these acute metabolic shifts trigger transient telomere shortening and activate ZSCAN4, a pluripotency-associated regulator of telomeres, followed by telomere re-elongation as cells adopt a more glycolytic
metabolic profile. Our findings reveal a feedback mechanism in which metabolism-induced telomere stress engages ZSCAN4 as a protective response, thereby linking metabolic state to telomere homeostasis during early developmental progression.
metabolic profile. Our findings reveal a feedback mechanism in which metabolism-induced telomere stress engages ZSCAN4 as a protective response, thereby linking metabolic state to telomere homeostasis during early developmental progression.
Date Issued
2025-12-23
Date Acceptance
2025-11-12
Citation
Cell reports, 2025, 44 (12)
ISSN
2211-1247
Publisher
Elsevier
Journal / Book Title
Cell reports
Volume
44
Issue
12
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1016/j.celrep.2025.116654
Publication Status
Published
Article Number
ARTN 116654
Date Publish Online
2025-12-10