Pluto Bioinformatics

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

Bulk RNA sequencing

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

View this experiment on Pluto Bioinformatics