NADPH levels affect cellular epigenetic state by inhibiting HDAC3-Ncor complex
NADPH levels affect cellular epigenetic state by inhibiting HDAC3-Ncor complex
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NADPH 水平通过抑制 HDAC3-Ncor 复合物影响细胞表观遗传状态
DOI：
10.1038/s42255-020-00330-2
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发表时间：
2021-01-18
影响因子：
20.8
通讯作者：
Du, Wenjing
中科院分区：
文献类型：
--
作者：
Li, Wei;Kou, Junjie;Du, Wenjing
Li等人报道了NADPH作为HDAC 3的抑制剂的非代谢作用，从而将NADPH水平与细胞的表观遗传状态联系起来。在这里，我们报告了代谢独立的功能，NADPH在调节表观遗传状态和转录。我们发现，通过沉默苹果酸酶或葡萄糖-6-磷酸脱氢酶实现的细胞NADPH水平的降低损害了脂肪细胞和肿瘤细胞中的全局组蛋白乙酰化和转录。这些作用可以通过补充外源性NADPH或通过抑制组蛋白脱乙酰酶3（HDAC 3）来逆转。在机制上，NADPH直接与HDAC 3相互作用，并中断HDAC 3与其共激活核受体辅阻遏物2（Ncor2; SMRT）或Ncor1之间的关联，从而损害HDAC 3激活。有趣的是，NADPH和肌醇四磷酸分子Ins（1，4，5，6）P-4似乎与HDAC 3上的相同结构域结合，其中NADPH对HDAC 3的亲和力高于Ins（1，4，5，6）P-4。因此，虽然Ins（1，4，5，6）P-4促进HDAC3-Ncor复合物的形成，NADPH抑制它。总的来说，我们的研究结果揭示了一个以前未确定的和代谢独立的作用，NADPH在控制表观遗传变化和基因表达作为内源性抑制剂HDAC3。
Li et al. report a non-metabolic role of NADPH as an inhibitor of HDAC3, thus linking NADPH levels with the epigenetic state of a cell.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)P-4 appear to bind to the same domains on HDAC3, with NADPH having a higher affinity towards HDAC3 than Ins(1,4,5,6)P-4. Thus, while Ins(1,4,5,6)P-4 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.