Résumé
Position effect variegation (PEY) is an archetypal epigenetic phenomenon in which a gene abnormally located close to heterochromatin is stochastically silenced in a proportion of cells that would normally express it. First described in Drosophila we have developed a mammalian model for PEY using transgenes in mice. Using this system we have found that the GAA-triplet repeat expansions that aberrantly silence the Frataxin gene in the neurodegenerative disease Friedreich's ataxia can induce PEY and that the Frataxin gene in cells from patients and a mouse model can be reactivated using a class III HDAC inhibitor, Nicotinamide, suggesting a novel therapy for this currently incurable disease. Moreover, using transgenic mouse PEY we discovered a difference in heterochromatin-mediated silencing between males and females which is due to sex-chromosome complement rather than gender – this finding has implications for understanding sex bias in disease susceptibility.
