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The molecular mechanisms of reduced frataxin (<i>FXN</i>) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the <i>FXN</i> locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human <i>FXN</i>-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing <i>FXN</i> expression. Overall, our results suggest that histone methylation is important in the regulation of <i>FXN</i> expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Original publication




Journal article


The Journal of biological chemistry

Publication Date





17973 - 17985


Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.