Besides length per se, CpG sites, repeats of cytosine followed by guanine, are often present in 5′UTRs. These regions can undergo cytosine methylation, an epigenetic modification that promotes gene silencing by recruiting proteins involved in gene repression of by inhibiting the binding of transcription factors.24 The higher the number of CpG sites in a 5′UTR, the higher the probability that the gene expression will be downregulated as a consequence of cytosine methylation. For example, fragile X syndrome, a genetic disorder characterized by several intellectual disabilities, is caused by the expansion of a CGG-repeat sequence in the 5′UTR of the FMR1 gene. Expansion to >200 copies of the CGG-repeat leads to hypermethylation of FMR1 and silencing of this gene, resulting in an insufficient amount of fragile X mental retardation protein that is pivotal for neuronal development.25
