Amphithéâtre Guillaume Budé, Site Marcelin Berthelot
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Abstract

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.

References

Chan P.K., Torres R., Yandim C., Law P.P., Khadayate S., Mauri M., Grosan C., Chapman-Rothe N., Giunti P., Pook M., Festenstein R., (2013), "Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by vitamin B3", Hum Mol Genet.

Wijchers P.J., Yandim C., Panousopoulou E., Ahmad M., Harker N., Saveliev A., Burgoyne P.S., and Festenstein R., (2010), "Sexual dimorphism in mammalian au tosomal gene regulation is determined not only by Sry but by sex chromosome complemen as weil", Dev Cell 19, 477-484.

Speaker(s)

Richard Festenstein

MRC Clinical Sciences Centre, Imperial College School of Medicine, London, UK