5-methylcytosine residues within the Frataxin (FXN) locus (5mC at FXN locus)

5-methylcytosine (5mC) residues within the Frataxin (FXN) locus are epigenetic modifications that play a central role in the pathogenesis of Friedreich's Ataxia (FRDA) (Evans-Galea et al., 2012, PubMed: 22535187). In FRDA, the expansion of GAA triplet repeats in the first intron of the FXN gene leads to the recruitment of DNA methyltransferases, resulting in hypermethylation of the CpG sites surrounding the expansion (Al-Mahdawi et al., 2008, PubMed: 18263603). This hypermethylation contributes to the formation of heterochromatin and the subsequent transcriptional silencing of the FXN gene, leading to a deficiency of the frataxin protein (Sandhu et al., 2011, PubMed: 21858144). Frataxin is essential for mitochondrial iron-sulfur cluster biogenesis, and its loss causes oxidative stress and mitochondrial dysfunction (Rotig et al., 1997, PubMed: 9103193). Therapeutic interventions targeting these 5mC residues, such as site-specific epigenetic editing using CRISPR-dCas9-TET1, aim to demethylate the locus and reactivate FXN expression (Ouellette et al., 2022, PubMed: 35145144). Restoring frataxin levels is considered a primary goal for treating the progressive neurological and cardiac symptoms of FRDA.

Other names

FXN DNA methylationMethylated CpG sites in FXN intron 1Epigenetic silencing of Frataxin5-mC at FXN geneFXN hypermethylation

DNA demethylation and removal of repressive epigenetic marks to restore Frataxin gene expression.