Pyridine nucleotides regulate gene expression and cellular metabolisms

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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.