FIGURE 2.

Hypothetical disease model of the role of the common epigenetic signature in repeat instability and disease phenotype. (A) Disease-causing nucleotide repeats typically have higher GC content, more CpG islands and more CTCF sites compared to non-disease-causing repeats in the genome. Typically, a TAD boundary will be present near disease-causing repeats. (B) Methylation near the nucleotide repeat results in increased repeat instability, potentially through a loss of CTCF binding, which is also associated with increased repeat instability. Additionally, the mismatch repair pathway, of which MSH2 and MSH3 are the main players at repeats, interacts with the hairpin structures formed at the repeat region and causes repeat instability. The close proximity of methylation and mismatch repair proteins to repeat regions could suggest that epigenetics and the mismatch repair machinery play a cooperative role regulating repeat instability.