Polycomb group complexes are recruited to reactivated FMR1 alleles in Fragile X syndrome in response to FMR1 transcription

The FMR1 geneis subject to repeat mediated-gene silencingwhentheCGG-repeat tract in the 5' UTR exceeds 200 repeat units. This results in Fragile X syndrome, the most common heritable cause of intellectual disability and a major cause of autism spectrum disorders. The mechanism of gene silencing is not fully understood, and efforts to reverse this gene silencing have had limited success. Here, we show that the level of trimethylation of histone H3 on lysine 27, a hallmark of the activity of EZH2, a component of repressive Polycomb Group (PcG) complexes like PRC2, is increased on reactivation of the silenced allele by either the DNA demethylating agent 5-azadeoxycytidine or the SIRT1 inhibitor splitomicin. The level of H3K27me3 increases and decreases in parallel with the FMR1 mRNA level. Furthermore, reducing the levels of the FMR1 mRNA reduces the accumulation of H3K27me3. This suggests a model for FMR1 gene silencing in which the FMR1 mRNA generated from the reactivated allele acts in cis to repress its own transcription via the recruitment of PcG complexes to the FMR1 locus.