Trends in Molecular Medicine
ReviewEpigenetic modifications in trinucleotide repeat 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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2020, Journal of Biological ChemistryCitation Excerpt :They can lead to the formation of repressive histone marks, such as histone H3 Lys-9 and histone H4 Lys-20 trimethylation, decreased histone acetylation, and changes in DNA methylation. These epigenetic changes often contribute to disease phenotypes, as they can alter gene expression patterns (469, 470). The chromatin environment, in turn, can promote or inhibit repeat instability.
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2020, RNA-Based Regulation in Human Health and DiseaseRatiometric electrochemical biosensor based on Exo III-Assisted recycling amplification for the detection of CAG trinucleotide repeats
2019, Biosensors and BioelectronicsCitation Excerpt :Abnormal expression of the GAA trinucleotide repeat causes Friedreich's ataxia, which is present in the 5′ untranslated region of the FMR1 gene. The CGG trinucleotide repeat is associated with fragile X syndrome (Dürr et al., 1996; Evansgalea et al., 2013; López Castel et al., 2010; Lin et al., 2015; Mirkin, 2007; Sutherland and Richards, 1995). Furthermore, a common feature of the diseases caused by amplification of trinucleotide repeat is the phenomenon of the hereditary prevalence which refers to the presence of certain genetic diseases for several generations: in this case, their associated symptoms are increasingly severe generation, while their onset time is one generation earlier than one generation (Lange and Mcinnis, 2002).
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2018, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Epigenetic modifications have been reported in several repeat expansion disorders, including DM1 [29,30], either as a mechanism to explain somatic repeat instability or transcriptional alterations in the disease genes [31]. In particular, significant correlations between clinical features, stability of repetitive DNA, gene expression, chromatin profile, and DNA methylation that occur in regions surrounding the expansion repeat disease have been demonstrated [32]. In DM1 patients, for example, the expanded allele of DMPK (Dystrophia Myotonica Protein Kinase; MIM #605377) gene shows a differential status of methylation [29,30].