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Series GSE145115 Query DataSets for GSE145115
Status Public on Oct 08, 2020
Title Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design 24 samples derived from two cell lines; a Friedrich's ataxia cell line (GM04078) and a healthy control line (GM03440). Untreated, DMSO treated, inactive compound treated and A-196 treated (3 different concentrations) analysed. Three cell culture replicates of each condition included.
A-196 is the lead compound
SGC2043 is the inactive structural analogue of A-196
 
Contributor(s) Vilema-Enríquez G, Quinlan R, Kilfeather P, Mazzone R, Saqlain S, del Molino del Barrio I, Donato A, Corda G, Li F, Vedadi M, Németh A, Brennan P, Wade-Martins R
Citation(s) 33028632
Submission date Feb 11, 2020
Last update date Jan 07, 2021
Contact name Gabriela Vilema-Enríquez
Organization name University of Oxford
Department Physiology, Anatomy and Genetics
Lab Molecular Neurodegeneration
Street address South Parks Road
City Oxford
ZIP/Postal code OX13QX
Country United Kingdom
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (24)
GSM4306696 GM78dmso1
GSM4306697 GM78dmso2
GSM4306698 GM78dmso3
Relations
BioProject PRJNA606059
SRA SRP248255

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE145115_counts_all_samples_normalised.txt.gz 3.0 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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