Review
Epigenetic modifications in trinucleotide repeat diseases

https://doi.org/10.1016/j.molmed.2013.07.007Get rights and content

Highlights

  • Up-to-date overview of the epigenetic changes in trinucleotide repeat (TNR) disease.

  • Understanding the link between TNR disease epigenetic profile and clinical outcome.

  • Discuss the future potential of epigenetic biomarkers and therapies for TNR disease.

Accumulating evidence supports the important role for epigenetic changes in modulating clinical parameters of complex disorders, including neurodegenerative disease. Several conditions, including fragile X syndrome and Huntington's disease are caused by trinucleotide repeat (TNR) expansions in or near specific genes. Highlighting the link between epigenetic disruption and disease phenotype, recent studies have established significant correlations between clinical features, expansion size, gene expression, the chromatin profile, and DNA methylation in regions surrounding the TNR. Given the debilitating and sometimes fatal consequences of TNR disorders, understanding how an altered epigenetic profile impacts clinical outcome warrants further attention, and could provide key insights for developing novel epigenetic therapies and biomarkers. This review presents the current evidence of epigenetic changes in several TNR diseases.

Section snippets

Epigenetics and disease

Epigenetic mechanisms encompass a range of regulatory factors that modify the activity state of underlying DNA in the absence of changes to the primary DNA sequence [1]. This includes the regulation of genes, with differences in overall epigenetic profile (the epigenome) and associated gene expression profile, contributing to the wide range of different cell and tissue types in the body. DNA methylation is the most widely studied epigenetic phenomenon and occurs almost exclusively in the

Epigenetic alterations in non-coding TNR diseases

Broadly speaking, TNR diseases can be classified into those involving poly-glutamine (poly-Q) expansions in coding regions and those with TNRs located in non-coding regions, such as introns and 5′ or 3′ untranslated regions (UTRs; Table 1).

Huntington's disease (HD)

HD is the most common TNR-associated disease with a prevalence estimated at 12.4 per 100 000 89, 90. HD is an autosomal dominant, progressive neurodegenerative disorder which can result in involuntary movements (chorea), dementia, and, in some affected individuals, psychiatric symptoms. Subtle involuntary movements and oculomotor dysfunction may occur years before diagnosis, but typically symptoms begin to emerge during young adulthood with diagnosis during the third or fourth decade of life 91,

Concluding remarks

Mounting data implicate epigenetic changes in TNR disease etiology, including age of onset, disease trajectory, and severity of phenotype. Understanding the link between the epigenetic profile and clinical outcome will provide novel insights into TNR disease pathobiology and may facilitate the development of much-needed tools in the clinic. The molecular mechanisms underlying TNR disease pathology are diverse, ranging from gene silencing through to the production of toxic RNA and protein.

Acknowledgments

The authors are funded by the National Health and Medical Research Council of Australia (Project Grant APP1048795 to M.B.D. and M.V.E-G.; Practitioner Fellowship to M.B.D.; Senior Research Fellowship to R.S.); the Australian Research Council (FT3 Future Fellowship to A.J.H.); and the Victorian Government Operational Infrastructure Support Program.

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