| http://purl.uniprot.org/citations/33028632 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33028632 | http://www.w3.org/2000/01/rdf-schema#comment | "The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's 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 FXN expression and represent a novel therapeutic target. Using a human FXN-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 FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.ra120.015533"xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Li F."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Nemeth A.H."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Vedadi M."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Wade-Martins R."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Quinlan R."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Brennan P.E."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Donato A."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Corda G."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Mazzone R."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Del Molino Del Barrio I."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Kilfeather P."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Saqlain S."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/author | "Vilema-Enriquez G."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/date | "2020"xsd:gYear |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/pages | "17973-17985"xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/title | "Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells."xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://purl.uniprot.org/core/volume | "295"xsd:string |
| http://purl.uniprot.org/citations/33028632 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33028632 |
| http://purl.uniprot.org/citations/33028632 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/33028632 |
| http://purl.uniprot.org/uniprot/#_B7WNX0-mappedCitation-33028632 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33028632 |
| http://purl.uniprot.org/uniprot/#_A0A8V8TQB9-mappedCitation-33028632 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33028632 |