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

Interleukin (IL)-1 b is a pleiotropic cytokine implicated in a variety of activities, including damage of insulin-producing cells, brain injury, or neuromodulatory responses. Many of these effects are mediated by nitric oxide (NO) produced by the induction of NO synthase (iNOS) expression. We report here that IL-1 b provokes a marked repression of genes, such as fragile X mental retardation 1 (FMR1) and hypoxanthine phosphoribosyltransferase (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 FMR1 CpG island can be reverted by demethylating agents which, in turn, produce the recovery of gene expression. The effects of IL-1 b and NO appear to be exerted through activation of DNA methyltransferase (DNA MeTase). Although exposure of the cells to NO does not increase DNA MeTase gene expression, the activity of the enzyme selectively increases when NO is applied directly on a nuclear protein extract. These findings reveal a previously unknown effect of IL-1 b and NO on gene expression, and demonstrate a novel pathway for gene silencing based on activation of DNA MeTase by NO and acute modification of CpG island methylation

May anomalous X chromosome methylation be responsible for the spontaneous abortion of a male foetus?

Pregnancy loss is an important reproductive problem which appears to be highly associated with genetic factors. A spontaneous abortion occurred before prenatal diagnosis could be performed, in a woman who carried a fragile X full mutation. DNA extracted from formalin-fixed para ffin-embedded chorionic villi preparations indicated that it was a male embryo with an apparently methylated X chromosome. The previous analysis of the family showed that her daughter, who also carried a full mutation, exhibited an extremely skewed X inactivation of the normal allele (100%) and a severe fragile X phenotype. Thus, we speculate that the aberrant pattern of X chromosome methylation in this family may provoke the spontaneous miscarriage of this pregnancy that could be explained by at least partial inactivation of the unique X chromosome in a male foetus. Spontaneous abortion occurs quite frequently in humans, and recurrent pregnancy loss is a significant problem in women’s health (Christiansen 2006). Many cases of spontaneous abortion defy diagnosis and genetic factors have been proposed as a major contribution (Lanasa and Hogge 2000; Sierra and Stephenson 2006). The X chromosome inactiva tion (XCI) is the process in which one of the two X chromosomes present in each cell of female mammals is inactivated during early embryogenesis, to achieve dosage compensation with males (Avner and Heard 2001; Heard 2004). Initial steps of XCI involve a ‘counting process’, which senses the X chromosome/autosome ratio that restricts XCI to female embryos and, thereafter, the choice of which chromosome is inactivated (Morey et al . 2004).Skewed XCI leads to an expression of X-linked recessive disorders in females (Plenge et al. 2002; Mart´ınez et al. 2005; Renault et al. 2007). Another form of X-inactivation called meiotic sex chromosome inactivation (MSCI), takes place in males, during spermatogenesis and is a manifestation of the general meiotic-silencing mechanism (Turner 2007). In this study, we report the spontaneous abortion of a male foetus with an apparently methylated X chromosome, and propose that anomalous inactivation of its uniqueX chromosome could explain nonviability of the embryo and pregnancy loss. Therefore, we strongly suggest, as a follow up, that the methylation status of the X chromosome be tested in early spontaneous abortion of males in the absence of any other known genetic or nongenetic cause

Emerging topics in FXTAS

This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013