PLX045690

GSE145115: Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreichs ataxia patient cells

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreichs ataxia (FRDA) are linked to epigenetic modification of the FXN 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 expression of FXN and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we first 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 protein by approximately 1.5-fold in the reporter cell line and in several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells (PMBCs). SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.47.8%) perturbation in genome-wide expression was observed. Finally, medicinal chemistry structural activity relationship (SAR) analysis resulted in the synthesis of novel small molecules with a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation may be important in the regulation of expression of FXN, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA. SOURCE: Gabriela Vilema-EnríquezMolecular Neurodegeneration University of Oxford