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SIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome

Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genetics (Impact Factor: 8.17). 03/2008; 4(3):e1000017. DOI: 10.1371/journal.pgen.1000017
Source: PubMed

ABSTRACT Author Summary
Fragile X syndrome is the leading cause of heritable intellectual disability. The affected gene, FMR1, encodes FMRP, a protein that regulates the synthesis of a number of important neuronal proteins. The causative mutation is an increase in the number of CGG•CCG-repeats found at the beginning of the FMR1 gene. Alleles with >200 repeats are silenced. The silencing process involves DNA methylation as well as modifications to the histone proteins around which the DNA is wrapped in vivo. Treatment with 5-azadeoxycytidine, a DNA methyltransferase inhibitor, reactivates the gene. However, this reagent is toxic and since no DNA demethylase has been found in humans, methylation inhibitors are not useful in cells like neurons that no longer divide. We show here that splitomicin is also able to reactivate the Fragile X allele. It does so by inhibiting a protein deacetylase, SIRT1, thus favoring the action of another enzyme, hMOF that reverses the SIRT1 modification. We also found that 5-azadeoxycytidine acts, at least in part, by reversing the effect of SIRT1. However, since splitomicin reactivation occurred without DNA demethylation, DNA replication is not necessary for its efficacy. Thus, unlike DNA methylation inhibitors, SIRT1 inhibitors may be able to reactivate Fragile X alleles in neurons.

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