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

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

doi:10.1038/s42255-020-00330-2

Cited by 43 publications

(31 citation statements)

References 52 publications

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“…Since the C-terminus can be phosphorylated by several kinases (Sengupta and Seto, 2004; Seo et al, 2019; Tsai and Seto, 2002; Zhang et al, 2021; Zhang et al, 2005), it suggests that the HDAC3-DAD domain interaction is regulated by signaling. Furthermore, a recent study showed that NADPH inhibits HDAC3-DAD domain complex formation by competing with IP4 for binding to HDAC3 (Li et al, 2021b). Thus, metabolic state and cell signaling regulate the balance between DAD-domain bound and unbound HDAC3, which may be a mechanism to control its transcriptional repressor activity.…”

Section: Discussionmentioning

confidence: 99%

Separation of transcriptional repressor and activator functions in HDAC3

Tang

Regadas

Беликов

et al. 2022

Preprint

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The histone deacetylase HDAC3 is associated with the NCoR/SMRT co-repressor complex and its canonical function is in transcriptional repression, but it can also activate transcription. Here we show that the repressor and activator functions of HDAC3 can be genetically separated in Drosophila. A lysine substitution in the N-terminus (K26A) disrupts its catalytic activity and activator function, whereas a combination of substitutions (HEBI) abrogating the interaction with SMRTER enhance repressor activity beyond wild-type in the early embryo. We conclude that the critical functions of HDAC3 in embryo development involve catalytic-dependent gene activation and non-enzymatic repression by several mechanisms, including tethering of loci to the nuclear periphery.

show abstract

Section: Discussionmentioning

confidence: 99%

Separation of transcriptional repressor and activator functions in HDAC3

Tang

Regadas

Беликов

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, it is likely that only a small fraction of the interactions between these central cellular processes have been characterized. Recently, a new interaction between the key redox metabolite NADPH and HDAC3 was discovered in adipocytes [64]. Novel high throughput functional genomics screening methods have identified HDAC6 as a regulator of glycolysis [65].…”

Section: Discussionmentioning

confidence: 99%

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

2021

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Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.

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“…The PPP is a metabolic branch stemming from glycolysis, generating NADPH and ribose 5-phosphate (Ru-5-P). Although NADPH is primarily utilized as a reducing entity, a non-canonical function of NADPH in modulating cellular epigenetics has recently emerged (Li et al, 2021b). NADPH inhibits HDAC3 activation through direct interaction, interfering with the association between HDAC3 and its coactivator, NCOR1/2.…”

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

“…NADPH inhibits HDAC3 activation through direct interaction, interfering with the association between HDAC3 and its coactivator, NCOR1/2. Furthermore, NADPH competes with inositol tetraphosphate, Ins(1,4,5,6)P4, for HDAC3 binding and suppresses HDAC3 activation (Li et al, 2021b). Moreover, it was observed that in cisplatin-resistant cancer cells, Ins(1,3,4,5)P4 competes with NADPH for the binding of NADPH oxidase 4 (NOX4), suppresses NOX4 activity, and alleviates cellular oxidative stress to support tumor growth under chemotherapy (Pan et al, 2019).…”

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%