PubReading [252] - Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation - L. Rodden, S. Bidichandani et al.

<p><strong>Friedreich ataxia</strong> (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the <em>FXN </em>gene. The expanded repeat induces repressive <strong>histone</strong> changes and <strong>DNA hypermethylation</strong>, which result in epigenetic silencing and <em>FXN </em>transcriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silenced <em>FXN </em>gene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somatic <em>FXN </em>molecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same <strong>PBMC</strong>s from this cohort with HDACi-109 significantly increased <em>FXN </em>transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated <em>FXN </em>molecules, supporting the model that <em>FXN </em>reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated <em>FXN </em>molecules are relatively resistant to reactivation. <em>FXN </em>reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic <strong>epigenetic heterogeneity</strong>.</p><p><em>doi: 10.3389/fnins.2021.752921 - 2021</em></p>