Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated <i>FMR1</i> Alleles in Fragile X Syndrome Patient Derived Cells
2020
Kumari, Daman | Sciascia, Nicholas | Usdin, Karen
In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the <i>FMR1</i> gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of <i>FMR1</i> silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the <i>FMR1</i> gene in FXS patient cells and is thus a potential druggable target. However, its contribution to the silencing process is unclear. Here, we studied the effect of small molecule inhibitors of H3K9 methylation on <i>FMR1</i> expression in FXS patient cells. Chaetocin showed a small effect on <i>FMR1</i> gene reactivation and a synergistic effect on <i>FMR1</i> mRNA levels when used in combination with AZA. Additionally, chaetocin, BIX01294 and 3-Deazaneplanocin A (DZNep) were able to significantly delay the re-silencing of AZA-reactivated <i>FMR1</i> alleles. These data are consistent with the idea that H3K9 methylation precedes DNA methylation and that removal of DNA methylation is necessary to see the optimal effect of histone methyl-transferase (HMT) inhibitors on <i>FMR1</i> gene expression. Nonetheless, our data also show that drugs targeting repressive H3K9 methylation marks are able to produce sustained reactivation of the <i>FMR1</i> gene after a single dose of AZA.
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