The exit of naive pluripotency contains a metabolism-induced checkpoint for telomere homeostasis
Year: 2025
Type: 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 naive to formative pluripotent state. We show that the exit of naive 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.
Source: Cell Reports
Authors: Roshni A. de Souza, David Barneda, Donja Karimlou, Nick G.P. Bovee, Yuhan Zheng, Eveline J.E.M. Kahlman, Clara Lopes Novo, James K. Ellis, Bryony J. Leeke, Songyang Li, Megha Prakash Bangalore, Zijing Liu, Bebiana C. Sousa, Andrea F. Lopez-Clavijo, Joop H. Jansen, Mauricio Barahona, Michelle Percharde, Hector C. Keun, Mark Christian, Hendrik Marks, Véronique Azuara
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Institute on Handicapped Research, Genesis Research Trust, UK Research and Innovation, Imperial College London, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Tommy's National Centre for Miscarriage Research, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G146373944, G2019866840, Role of CIDE proteins in lipid droplet formation and adipocyte metabolism, Trafficking, storage and timely release of lipids: unfolding the fundamental mechanisms underlying metabolic reprogramming in pluripotent stem cells., G3026550412, G3454527460, Trafficking, storage and timely release of lipids: unfolding the fundamental mechanisms underlying metabolic reprogramming in pluripotent stem cells., G4577827460, G8151690839
OpenAlex ID: W4417212834