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DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

1
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, 80131 Naples, Italy
2
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
*
Author to whom correspondence should be addressed.
Genes 2020, 11(6), 684; https://doi.org/10.3390/genes11060684
Received: 13 May 2020 / Revised: 18 June 2020 / Accepted: 19 June 2020 / Published: 22 June 2020
(This article belongs to the Special Issue DNA Methylation in Health and Diseases)
Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders. View Full-Text
Keywords: hypermethylated expansion disorders; DNA hypermethylation-induced transcriptional silencing; neurological and neuromuscular diseases; 5-methylcytosine; CpG site; diagnostic methods; molecular targeted therapy hypermethylated expansion disorders; DNA hypermethylation-induced transcriptional silencing; neurological and neuromuscular diseases; 5-methylcytosine; CpG site; diagnostic methods; molecular targeted therapy
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MDPI and ACS Style

Poeta, L.; Drongitis, D.; Verrillo, L.; Miano, M.G. DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms. Genes 2020, 11, 684.

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