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

Wei Li, Junjie Kou, Junying Qin, Li Li, Zhenxi Zhang, Ying Pan, Yi Xue, Wenjing Du

Nature metabolism 2021 Jan

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NADPH has long been recognized as a key cofactor for antioxidant defence and reductive biosynthesis. Here we report a metabolism-independent function of NADPH in modulating epigenetic status and transcription. We find that the reduction of cellular NADPH levels, achieved by silencing malic enzyme or glucose-6-phosphate dehydrogenase, impairs global histone acetylation and transcription in both adipocytes and tumour cells. These effects can be reversed by supplementation with exogenous NADPH or by inhibition of histone deacetylase 3 (HDAC3). Mechanistically, NADPH directly interacts with HDAC3 and interrupts the association between HDAC3 and its co-activator nuclear receptor corepressor 2 (Ncor2; SMRT) or Ncor1, thereby impairing HDAC3 activation. Interestingly, NADPH and the inositol tetraphosphate molecule Ins(1,4,5,6)P4 appear to bind to the same domains on HDAC3, with NADPH having a higher affinity towards HDAC3 than Ins(1,4,5,6)P4. Thus, while Ins(1,4,5,6)P4 promotes formation of the HDAC3-Ncor complex, NADPH inhibits it. Collectively, our findings uncover a previously unidentified and metabolism-independent role of NADPH in controlling epigenetic change and gene expression by acting as an endogenous inhibitor of HDAC3.

Citation

Wei Li, Junjie Kou, Junying Qin, Li Li, Zhenxi Zhang, Ying Pan, Yi Xue, Wenjing Du. NADPH levels affect cellular epigenetic state by inhibiting HDAC3-Ncor complex. Nature metabolism. 2021 Jan;3(1):75-89