Altering metabolism programs cell identity via NAD+-dependent deacetylation
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.
Authors
- Indra Heckenbach (ORCID: https://orcid.org/0000-0001-7038-4677)
- Michael L. Nielsen (ORCID: https://orcid.org/0000-0002-0067-9039)
- Karolina Sulek (ORCID: https://orcid.org/0000-0002-7117-3756)
- Catherine G. Vasilopoulou (ORCID: https://orcid.org/0000-0002-6622-1979)
- Molly Lowndes (ORCID: https://orcid.org/0000-0003-3692-7847)
- Jonas T. Treebak (ORCID: https://orcid.org/0000-0003-1488-7012)
- Victor Solis‐Mezarino (ORCID: https://orcid.org/0000-0002-5766-7418)
- Sarah Lundregan (ORCID: https://orcid.org/0000-0002-4971-6208)
- Ala Trusina (ORCID: https://orcid.org/0000-0003-1945-454X)
- Joshua M. Brickman (ORCID: https://orcid.org/0000-0003-1580-7491)
- Silvia Raineri (ORCID: https://orcid.org/0000-0003-4381-1033)
- Morten Dall (ORCID: https://orcid.org/0000-0002-8577-3162)
- José Alejandro Romero Herrera (ORCID: https://orcid.org/0000-0002-4765-2087)
- Robert A. Bone
- Alba Redó Riveiro (ORCID: https://orcid.org/0000-0002-7015-2486)
- Matthias Mann (ORCID: https://orcid.org/0000-0003-1292-4799)
- Moritz Völker-Albert (ORCID: https://orcid.org/0009-0003-2946-1169)
- Luna Lynge Malzard
- Sandra Koigi
- Florian Meier (ORCID: https://orcid.org/0000-0003-4729-175X)
Institutions
- University of Copenhagen (DK)
- Novo Nordisk Foundation (DK)
- ift Rosenheim (DE)
- Max Planck Institute of Biochemistry (DE)
- Novo Nordisk Foundation Center for Basic Metabolic Research
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s44318-025-00417-0
- Citations
- 2
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- European Commission
- National Research Foundation
- Danmarks Grundforskningsfond
- Lundbeckfonden
- Novo Nordisk
- Danish e-Infrastructure Cooperation
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research
- H. Lundbeck A/S
- Centro de Investigação em Biomedicina