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Analysis of FMR1 splicing in FXS iPSCs

ABSTRACT: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of FMRP that, with rare exceptions, results from CGG expansion in the promoter region of FMR1. The trinucleotide expansion has long been thought to induce epigenetic silencing of the FMR1 locus, resulting in complete loss of expression at the mRNA level. However, a recent study reported that FMR1 is transcribed in a substantial proportion of FXS tissues, yet due to mis-splicing, no FMRP protein is produced. The current study sought to independently validate this key finding in FXS iPSCs. FXS patient-derived iPSCs with a transcriptionally silenced FMR1 locus were treated with 5-AzadC for 48 hours to induce reactivation of the FMR1 locus. RNA was subsequently isolated from treated and untreated iPSCs and analyzed by RNA-sequencing. Our findings demonstrate that while FMR1 is reactivated following 5-AzadC treatment, no FMRP is expressed, likely due to mis-splicing of the FMR1 transcript. These results have important implications for understanding FXS pathogenesis and developing therapeutic strategies targeting the expanded FMR1 locus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307114 | GEO | 2026/05/20

REPOSITORIES: GEO

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Antisense Oligonucleotide Rescue of CGG Expansion-Dependent FMR1 Mis-Splicing in Fragile X Syndrome Restores FMRP

Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.

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Genome-wide analysis identifies aberrant methylation in Fragile X syndrome is specific to the FMR1 locus

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Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by the silence of FMR1. Hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients was thought to epigenetically silence FMR1. Here, we applied our previously developed DNA methylation editing tool to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/gRNA switched the heterochromatin status of the FMR1 promoter to an active chromatin status and subsequently restored FMR1 expression in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs showed a similar electrophysiological property as wild-type neurons, and maintained FMR1 expression for months after engrafting into the mouse brain. Reactivation of FMR1 can be achieved in FXS neurons with demethylation of the CGG expansion. Lastly, we showed that targeted demethylation of the FMR1 promoter can reactivate FMR1 as well suggesting potential therapeutic approaches for FXS.

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