NADPH levels affect cellular epigenetic state by inhibiting HDAC3-Ncor complex

Area of Science:

• Biochemistry
• Epigenetics
• Molecular Biology

Background:

• Nicotinamide adenine dinucleotide phosphate (NADPH) is crucial for antioxidant defense and biosynthesis.
• Its role beyond metabolism in cellular regulation remains largely unexplored.

Purpose of the Study:

• To investigate the metabolism-independent functions of NADPH.
• To elucidate NADPH's role in epigenetic regulation and gene transcription.

Main Methods:

• Silencing of malic enzyme or glucose-6-phosphate dehydrogenase to reduce NADPH levels.
• Assessing global histone acetylation and transcription in adipocytes and tumor cells.
• Investigating the interaction between NADPH, histone deacetylase 3 (HDAC3), and its co-activators (Ncor2, Ncor1).

Main Results:

• Reduced cellular NADPH impairs histone acetylation and transcription.
• Exogenous NADPH or HDAC3 inhibition reverses these effects.
• NADPH directly binds to HDAC3, inhibiting its association with co-activators Ncor2/Ncor1.
• NADPH competes with inositol tetraphosphate (Ins(1,4,5,6)P4) for binding to HDAC3, acting as an inhibitor.

Conclusions:

• NADPH plays a critical, metabolism-independent role in epigenetic regulation.
• NADPH acts as an endogenous inhibitor of HDAC3, modulating gene expression.
• This finding reveals a novel mechanism controlling epigenetic changes and transcription.