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Updated: Feb 5, 2026
06:07
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
3.1K
FMR1 RNA interaction with DNMT1 blocks DNA methylation at the FMR1 locus
Veronica Nobile1,2, Benedetta Niccolini1,2,3, Cecilia Pucci1
1Dipartimento di Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
NAR Molecular Medicine
|February 4, 2026
Summary
Unmethylated CGG expansions in the FMR1 gene prevent Fragile X Syndrome (FXS). DNMT1 binding to FMR1 mRNA or the gene locus regulates methylation, offering a target for FXS gene reactivation.
Area of Science:
- Genetics
- Epigenetics
- Molecular Biology
Background:
- Fragile X Syndrome (FXS) is caused by CGG triplet expansion (>200 repeats) in the FMR1 gene, leading to DNA methylation and gene silencing.
- Rare individuals with large CGG expansions (>200) remain phenotypically normal due to unmethylated alleles, suggesting a protective mechanism.
Purpose of the Study:
- To investigate the hypothesis that active FMR1 transcription regulates locus DNA methylation via mRNA binding to DNMT1.
- To explore DNMT1 as a potential therapeutic target for reactivating FMR1 gene expression in FXS.
Main Methods:
- Assessed DNMT1 binding to FMR1 mRNA and the FMR1 locus in transcriptionally active versus FXS cells.
- Utilized specific drugs to modulate FMR1 transcription and observed corresponding DNMT1 binding.
- Demonstrated FMR1 gene reactivation using DNMT1-inhibiting aptamers in a proof-of-concept study.
Main Results:
- DNMT1 binds to FMR1 mRNA in transcriptionally active cells, preventing locus methylation.
- In FXS cells, DNMT1 binds to the FMR1 locus, causing gene silencing.
- Modulating FMR1 transcription with drugs altered DNMT1 binding patterns.
- DNMT1-inhibiting aptamers successfully reactivated the silenced FMR1 gene.
Conclusions:
- DNMT1 plays a dual role in FMR1 gene regulation, binding mRNA to prevent methylation or the locus to silence transcription.
- DNMT1 is a key molecular target for potential therapeutic strategies aimed at reactivating FMR1 expression in Fragile X Syndrome.
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