Abstract: Mutations in the MECP2 gene are found in a large proportion of girls
with Rett Syndrome. Despite extensive research, the principal role of MeCP2
protein remains elusive. Is MeCP2 a regulator of genes, acting in concert with
co-activators and co-repressors, predominantly as an activator of target genes
or is it a methyl CpG binding protein acting globally to change the chromatin
state and to supress transcription from repeat elements? If MeCP2 has no
specific targets in the genome, what causes the differential expression of
specific genes in the Mecp2 knockout mouse brain? We discuss the discrepancies
in current data and propose a hypothesis to reconcile some differences in the
two viewpoints. Since transcripts from repeat elements contribute to piRNA
biogenesis, we propose that piRNA levels may be higher in the absence of MeCP2
and that increased piRNA levels may contribute to the mis-regulation of some
genes seen in the Mecp2 knockout mouse brain. We provide preliminary data
showing an increase in piRNAs in the Mecp2 knockout mouse cerebellum. Our
investigation suggests that global piRNA levels may be elevated in the Mecp2
knockout mouse cerebellum and strongly supports further investigation of piRNAs
in Rett syndrome.
Keywords: Rett Syndrome, MeCP2, piRNAs, LINE 1, short RNAs
