Chromatin remodelling resulting from FraX premutation alleles
Fragile X syndrome is known to result from transcriptional silencing of the FMR1 gene.
This results from hypermethylation of the CGG repeat tract in the 5' untranslated region of FMR1, that occurswhen there is a large expansion of that repeat tract.
In contrast, smaller expansions of the tract, as in "premutations", cause the fragile X tremor ataxia syndrome (FXTAS). It is known that this results from overexpression (rather than the under-expression caused by hypermethylation) of the FMR1 gene, resulting in increased (and toxic) levels of the transcript.
For many years, the mechanism of overexpression of the gene that is associated with the premutations has not been explained.
Experiments in a Drosophila model of FXTAS, and in human premutation cell lines, have shown that the premutation alleles cause increased histone acetylation at the CGG repeat and that this results in the increased FMR1 gene transcription. More recently, it has been reported that the precise mechanism of pathogenicity may result, intriguingly, from an imbalance of the tissue distribution and expression levels between the many different splice-isoforms of FMR1 gene transcripts (messenger RNA molecules), rather than simply a general increase in FMR1 gene transcription in general.
