Epigenetic Mechanisms and Disease
How individual cells make the decision to switch genes ‘on’ and ‘off’ during the development of specific cell types and how they 'remember' this decision through cell division is central to the biology of multi-cellular organisms. Professor Festenstein studies factors that influence this decision and maintain it.
He has shown that where a gene is located in the mammalian chromosome has a large effect on the probability of switching it on or off. This phenomenon was first described in fruit flies and called Position Effect Variegation (PEV). His group identified DNA sequences that can promote or overcome this silencing and showed that the extent of gene inactivation is dependent on the amount of DNA packaging proteins. By investigating the hypothesis that such effects may play a role in some human diseases they have shown that abnormally large DNA triplet repeats can trigger aberrant gene silencing and that this silencing can be reversed providing potential novel therapies for currently untreatable diseases such as Freidreich's ataxia.
Heterochromatin is frequently associated with repetitive DNA sequences. Using a transgenic reporter gene we were able to show that triplet repeats that are expanded in neurogenetic diseases, including Friedreich’s ataxia, can trigger position effect variegation in vivo (Saveliev et al 2003). This opened up the possibility that the genetic modifiers of PEV (genes that encode chromatin modifiers) might also be disease modifiers in such ‘position-effect’ diseases. We then focused on Friedreich’s ataxia as a prototypic position-effect disease. We recently showed in model systems and primary cells from Friedreich’s ataxia patients that heterochromatin spreads on either side of the GAA-repeat expansion, silencing the Frataxin gene, which causes the disease. This silencing could be antagonised by the classical histone deacetylase inhibitor, nicotinamide (vitamin B3) thereby restoring Frataxin expression toward asymptomatic carrier levels (Chan et al 2013). These preclinical studies led to a clinical study in which high-dose nicotinamide was administered to Friedreich’s ataxia patients. The study revealed a dose-dependent increase in Frataxin levels accompanied by a reduction in heterochromatin modifications (Libri & Yandim et al 2014). This study provides proof-of-concept that an epigenetic modifier can be used to reactivate such a heterochromatinised gene in humans. The study was too short given the slowly progressive nature of Friedreich's ataxia to determine whether there was any clear-cut clinical benefit. Further studies are now being planned to determine whether administration of nicotinamide can be safely given for long periods and slow or arrest disease progression in Friedreich’s ataxia as there is currently no disease-modifying therapy for this condition. The study opens up the possibility that other diseases caused by a similar ‘epigenetic’ mechanisms may also be amenable to similar treatments.
Professor Festenstein is an associate of the Medical Research Council's Clinical Sciences Centre (www.csc.mrc.ac.uk) a member of the Division of Brain Sciences, Imperial College and an Honorary Consultant at the Imperial College Health Care Trust and the National Hospital for Neurology and Neurosurgery, Queen Square, London.
et al., 2014, Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study, The Lancet, Vol:384, ISSN:0140-6736, Pages:504-513
et al., 2013, Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreichs ataxia can be reduced upon HDAC inhibition by vitamin B3, Human Molecular Genetics, Vol:22, ISSN:0964-6906, Pages:2662-2675
et al., 2011, H3 Lysine 4 Is Acetylated at Active Gene Promoters and Is Regulated by H3 Lysine 4 Methylation, Plos Genetics, Vol:7, ISSN:1553-7404
et al., 2010, Sexual Dimorphism in Mammalian Autosomal Gene Regulation Is Determined Not Only by Sry but by Sex Chromosome Complement As Well, Developmental Cell, Vol:19, ISSN:1534-5807, Pages:477-484
Festenstein R, 2006, Breaking the silence in Friedreich's ataxia, Nature Chemical Biology, Vol:2, ISSN:1552-4450, Pages:512-513
et al., 2003, DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing, Nature, Vol:422, ISSN:0028-0836, Pages:909-913
et al., 2003, Modulation of heterochromatin protein 1 dynamics in primary mammalian cells, Science, Vol:299, ISSN:0036-8075, Pages:719-721
et al., 1996, Locus control region function and heterochromatin-induced position effect variegation, Science, Vol:271, ISSN:0036-8075, Pages:1123-1125