potential combinatorial regulation of DICER1, the down-regulated alcohol-responsive gene with the greatest over-representation of miRNA targeting events in our dataset, could have important implications for understanding the regulatory events taking place under chronic alcohol abuse. Dicer is a key ribonuclease that processes precursor miRNAs and siRNA into their short mature forms and its knockdown has resulted in reduced expression of mature miRNA (Kumar et al., 2007). Targeting and down-regulation of Dicer by miRNAs could represent an important negative feedback mechanism by which miRNAs control their own availability and avoid potentially detrimental effects of excess deregulation. Supporting this line of reasoning is the recent report by Tokumaru et al. (Tokumaru et al., 2008) describing the possible existence of a novel negative feedback loop between let-7 and Dicer that may play a role in the tuning of mature miRNA expression and carcinogenesis. In addition, it has been reported that the magnitude of change in levels of endogenous miRNAs that mediate regulation of gene expression often occur over a narrow range of only 20-30% (Hobert, 2007; Peter, 2010). In our study we also found that the alcohol-induced up-regulation of miRNAs was constrained in a similar range, with only a few miRNAs varying levels
