Methylation-dependent gene silencing induced by interleukin 1 beta via nitric oxide production

Interleukin (IL)-1 beta is a pleiotropic cytokine implicated in a variety o f activities, including damage of insulin-producing cells, brain injury, or neuromodulatory responses. Many of these effects are mediated by nitric ox ide (NO) produced by the induction of NO synthase (iNOS) expression. We rep ort here that IL-1 beta provokes a marked repression of genes, such as frag ile X mental retardation 1 (FMR1) and hypoxanthine phosphoribosyltransferas e (HPRT), having a CpG island in their promoter region. This effect can be fully prevented by iNOS inhibitors and is dependent on DNA methylation. NO donors also cause FMR1 and HPRT gene silencing. NO-induced methylation of F MR1 CpG island can be reverted by demethylating agents which, in turn, prod uce the recovery of gene expression. The effects of IL-1 beta and NO appear to be exerted through activation of DNA methyltransferase (DNA MeTase), Al though exposure of the cells to NO does not increase DNA MeTase gene expres sion, the activity oi-the enzyme selectively increases when NO is applied d irectly on a nuclear protein extract. These findings reveal a previously un known effect of IL-1 beta and NO on gene expression, and demonstrate a nove l pathway for gene silencing based on activation of DNA MeTase by NO and ac ute modification of CpG island methylation.