What genes might be regulated by ethanol in a Sir2-dependent manner? Drosophila Sir2 targets include, among others, those bound by the Hairy transcriptional repressor and the E(Z) histone methyltransferase complex that is involved in chromatin silencing (Bianchi-Frias et al., 2004; Furuyama et al., 2004). Association of Hairy with specific genomic loci is cell-type or developmental stage specific, suggesting that additional factors direct Hairy and by extension Sir2 to DNA. Studies of Hairy- and Sir2-dependent histone acetylation patterns in ethanol-exposed flies could provide candidate genes for the regulation of behavioral plasticity. Nuclear non-histone protein targets of mammalian Sir2 homolog SIRT1 include p53, FOXO proteins, and NFκB, and these evolutionarily conserved proteins may also play a role in regulating ethanol behavioral responses (Denu, 2005).
