Epigenetics of Myotonic Dystrophies: A Minireview

Abstract

Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the DMPK and CNBP genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype–phenotype correlations in DM patients.

Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies

“…Given their previously known significance in human disease, DNA methylation (DNAme) and regulatory microRNA (miRNA) profiles are suitable for characterization in DM1 by means of whole-genome epigenomics experimental strategies. To date, DNAme omics studies in DM1 have focused only on CpG islands surrounding the CTG repeat [69], mainly approached using pyrosequencing omics methodology.Accumulating evidence supports that hypermethylation levels are associated with DM1 pathogenesis, with different tissues and clinical forms being affected [69]. Only one genome-wide methylation study has been performed in DM1, involving also several other trinucleotide repeat disorders.…”

Myotonic Dystrophies: A Genetic Overview

“…This has been well-characterized in congenital DM1 with the role of DNA hypermethylation at the CTCF1 binding site, which was discussed above in the genetics section of this review article. A recent review article summarizes available evidence on the potential role of epigenetics in DM1 and DM2 [ 82 ]. DNA methylation upstream of the CTG repeats in blood DNA has been proposed as a marker of maternally inherited congenital DM1 [ 25 , 49 ].…”

Overview of the Complex Relationship between Epigenetics Markers, CTG Repeat Instability and Symptoms in Myotonic Dystrophy Type 1

“…The CTCF protein function as transcriptional activator or repressor but also as an insulator protein [ 46 , 47 , 97 , 98 ]. In DM1, the absence of CTCF binding due to CpG methylation, induces the loss of its insulator activity, eventually allowing the propagation of heterochromatin and thus the downregulation of DMPK and SIX5 genes for more details, see the review [ 99 ]. Recently, Yanovsky-Dagan et al identified a CpG-rich region, 650 bp upstream of the repeat, as an enhancer of SIX5 [ 100 ].…”