2025-04-25 コペンハーゲン大学(UCPH)
<関連情報>
- https://news.ku.dk/all_news/2025/04/researchers-create-super-stem-cells-seeing-potential-for-improved-fertility-treatment/
- https://www.embopress.org/doi/full/10.1038/s44318-025-00417-0
NAD+依存性脱アセチル化を介した代謝プログラムによる細胞のアイデンティティの変化 Altering metabolism programs cell identity via NAD+-dependent deacetylation
Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, and Joshua M Brickman
The EMBO Journal Published:25 April 2025
DOI:https://doi.org/10.1038/s44318-025-00417-0
Synopsis
How alterations in cell metabolism translate into specific developmental gene programs remains a major question. This study shows that forcing OXPHOS metabolism reprograms mouse embryonic stem cells (ESCs) to a more inner cell mass (ICM)-like state via deacetylation of of chromatin and specific transcription factors.
- Replacement of D-glucose by D-galactose in ESC media inhibits glycolysis in favor of enhanced OXPHOS metabolism.
- Enhanced OXPHOS metabolism reprograms ESCs to an early embryonic, ICM-like state.
- Enhanced metabolic ESCs (EMESCs) show increased NAD+-dependent Sirtuin activity and deacetylation of chromatin and ICM-specific transcription factors.
- Transcription factor deacetylation mediates increased occupancy at a subset of enhancers in EMM cultured ESCs.
Abstract
Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of d-glucose by d-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
