Altering metabolism programs cell identity via NAD⁺-dependent deacetylation

Area of Science:

• Cell Biology
• Metabolic Reprogramming
• Developmental Biology

Background:

• Cellular metabolism is intrinsically linked to gene regulation.
• Understanding how metabolic shifts influence cell identity is crucial for developmental biology.
• Embryonic stem cells (ESCs) possess unique metabolic characteristics that support pluripotency.

Purpose of the Study:

• To investigate how metabolic alterations can direct cellular identity in ESCs.
• To explore the role of oxidative phosphorylation (OXPHOS) in reprogramming ESCs towards an inner cell mass (ICM)-like state.
• To elucidate the molecular mechanisms linking metabolic changes to transcriptional programming.

Main Methods:

• Culturing ESCs in media with D-galactose instead of D-glucose.
• Measuring changes in cellular metabolism, focusing on glycolysis and OXPHOS.
• Analyzing histone and transcription factor acetylation levels.
• Assessing changes in gene expression and enhancer activity.

Main Results:

• Replacing D-glucose with D-galactose inhibited glycolysis and stimulated OXPHOS in ESCs.
• Enhanced OXPHOS activated NAD+-dependent Sirtuin deacetylases.
• Deacetylation of histones and transcription factors focused enhancer activity and reduced transcriptional noise.
• This metabolic shift promoted a developmental identity resembling the ICM.

Conclusions:

• Metabolic reprogramming, specifically enhancing OXPHOS, can induce a specific developmental cell identity in ESCs.
• The NAD+/NADH coenzyme ratio, modulated by OXPHOS, plays a key role in programming lineage-specific transcription.
• This mechanism suggests a paradigm for cellular rejuvenation through targeted metabolic and enzymatic activity.