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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
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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.
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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
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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
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Department |
Physiology, Anatomy and Genetics
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Lab |
Molecular Neurodegeneration
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Street address |
South Parks Road
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City |
Oxford |
ZIP/Postal code |
OX13QX |
Country |
United Kingdom |
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Platforms (1) |
GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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Samples (24)
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Relations |
BioProject |
PRJNA606059 |
SRA |
SRP248255 |
Supplementary file |
Size |
Download |
File type/resource |
GSE145115_counts_all_samples_normalised.txt.gz |
3.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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