DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms
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 rep...
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MDPI AG
2020-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/6/684 |
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| author | Loredana Poeta Denise Drongitis Lucia Verrillo Maria Giuseppina Miano |
| author_facet | Loredana Poeta Denise Drongitis Lucia Verrillo Maria Giuseppina Miano |
| author_sort | Loredana Poeta |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T18:57:08Z |
| format | Article |
| id | doaj.art-39f85c42253b4c22ba5e0b1a587532b8 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T18:57:08Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-39f85c42253b4c22ba5e0b1a587532b82023-11-20T04:38:45ZengMDPI AGGenes2073-44252020-06-0111668410.3390/genes11060684DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic MechanismsLoredana Poeta0Denise Drongitis1Lucia Verrillo2Maria Giuseppina Miano3Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, 80131 Naples, ItalyUnstable 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.https://www.mdpi.com/2073-4425/11/6/684hypermethylated expansion disordersDNA hypermethylation-induced transcriptional silencingneurological and neuromuscular diseases5-methylcytosineCpG sitediagnostic methods |
| spellingShingle | Loredana Poeta Denise Drongitis Lucia Verrillo Maria Giuseppina Miano DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms Genes hypermethylated expansion disorders DNA hypermethylation-induced transcriptional silencing neurological and neuromuscular diseases 5-methylcytosine CpG site diagnostic methods |
| title | DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms |
| title_full | DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms |
| title_fullStr | DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms |
| title_full_unstemmed | DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms |
| title_short | DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms |
| title_sort | dna hypermethylation and unstable repeat diseases a paradigm of transcriptional silencing to decipher the basis of pathogenic mechanisms |
| topic | hypermethylated expansion disorders DNA hypermethylation-induced transcriptional silencing neurological and neuromuscular diseases 5-methylcytosine CpG site diagnostic methods |
| url | https://www.mdpi.com/2073-4425/11/6/684 |
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