Pyridine nucleotides regulate gene expression and cellular metabolisms

我们发现了中性曲霉基因编码sirtuin同工酶（SirA），与酵母Sir2p的氨基酸同源性为47%。重组SirA表现出对烟酰胺敏感的NAD（+）依赖性HDAC活性，以及组蛋白H4的去乙酰化赖氨酸16残基（H4K16），表明SirA是真菌sirtuin的对应物。sirA的基因干扰物在ipnA和aflR及其转录本的基因启动子处积累了更多乙酰化的H4K16，产生了更多的青霉素G和sterigmatocystin，表明sirA去除了H4K16乙酰化，抑制了这些次级代谢产物基因的表达。添加烟酰胺核苷诱导细胞NAD+增加和次级代谢物产生减少，同时ipnA和aflR基因启动子上H4K16乙酰化水平降低，这在sirA基因干扰物中不明显。这些结果表明细胞NAD+通过SirA调节HDAC反应。

We found Aspergillus nidulans gene encoding a sirtuin isozyme (SirA) with an amino acid identity of 47% to yeast Sir2p. Recombinant SirA exhibited nicotinamide sensitive NAD(+)-dependent HDAC activity, and deacetylated lysine 16 residue of histone H4 (H4K16), indicating that SirA is a fungal sirtuin counterpart. Gene disruptant of sirA accumulated more acetylated H4K16 at the gene promoters of ipnA and aflR and their transcripts and produced more penicillin G and sterigmatocystin, indicating that SirA removes H4K16 acetylation and represses the expression of these secondary metabolite genes. The increased cellular NAD+ and the decreased secondary metabolite production induced by adding nicotinamide riboside accompanied decreased levels of H4K16 acetylation at the ipnA and aflR gene promoters, which was not evident in the sirA gene disruptant. These results indicate that cellular NAD+ modulates the HDAC reaction by SirA.