Sustained epigenetic reactivation in fragile X neurons with an RNA-binding small molecule Journal Article
| Authors: | Kam, C. W.; Dumelie, J. G.; Ciceri, G.; Yang, W. Y.; Disney, M. D.; Studer, L.; Jaffrey, S. R. |
| Article Title: | Sustained epigenetic reactivation in fragile X neurons with an RNA-binding small molecule |
| Abstract: | Background/Objectives: Fragile X syndrome (FXS) is a disease of pathologic epigenetic silencing induced by RNA. In FXS, an expanded CGG repeat tract in the FMR1 gene induces epigenetic silencing during embryogenesis. FMR1 silencing can be reversed with 5-aza-deoxyctidine (5-aza-dC), a nonspecific epigenetic reactivator; however, continuous administration of 5-aza-dC is problematic due to its toxicity. We describe an approach to restore FMR1 expression in FXS neurons by transient treatment with 5-aza-dC, followed by treatment with 2HE-5NMe, which binds the CGG repeat expansion in the FMR1 mRNA and could block the resilencing of the FMR1 gene after withdrawal of 5-aza-dC. Methods: This study uses immunofluorescence and fluorescent in situ hybridization (FISH) to measure whether FMR1 expression is maintained in FXS post-mitotic neurons treated with 2HE-5NMe. Genome-wide profiling of histone marks was used to monitor epigenetic changes and drug selectivity in response to 5-aza-dC followed by 2HE-5NMe treatment. Changes to dendritic morphology were visualized using confocal microscopy. Results: In this study, we find that 2HE-5Nme maintains FMR1 in a reactivated state after reactivation using 5-aza-dC in post-mitotic neurons. FMR1 reactivation in neurons results in the re-expression of FMRP and reversal of FXS-associated dendritic spine defects. Conclusions: These results demonstrate that an RNA-binding small molecule can achieve gene-specific epigenetic control and provide an approach for the restoration of FMRP in FXS neurons. |
| Keywords: | epigenetics; in-vitro; neurodegeneration; expression; stem-cells; inhibition; messenger-rna; fragile x syndrome; fmr1 gene; rna-binding small molecule; identify compounds; drosophila model; map2 |
| Journal Title: | Genes |
| Volume: | 16 |
| Issue: | 3 |
| ISSN: | 2073-4425 |
| Publisher: | MDPI |
| Date Published: | 2025-03-01 |
| Start Page: | 278 |
| Language: | English |
| ACCESSION: | WOS:001452175500001 |
| DOI: | 10.3390/genes16030278 |
| PROVIDER: | wos |
| PMCID: | PMC11942054 |
| PUBMED: | 40149430 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Wos |
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