Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism

Hum Genomics. 2013 Sep 16;7(1):19. doi: 10.1186/1479-7364-7-19.


Background: The MECP2 gene codes for methyl CpG binding protein 2 which regulates activities of other genes in the early development of the brain. Mutations in this gene have been associated with Rett syndrome, a form of autism. The purpose of this study was to investigate the role of evolutionarily conserved cis-elements in regulating the post-transcriptional expression of the MECP2 gene and to explore their possible correlations with a mutation that is known to cause mental retardation.

Results: A bioinformatics approach was used to map evolutionarily conserved cis-regulatory elements in the transcribed regions of the human MECP2 gene and its mammalian orthologs. Cis-regulatory motifs including G-quadruplexes, microRNA target sites, and AU-rich elements have gained significant importance because of their role in key biological processes and as therapeutic targets. We discovered in the 5'-UTR (untranslated region) of MECP2 mRNA a highly conserved G-quadruplex which overlapped a known deletion in Rett syndrome patients with decreased levels of MeCP2 protein. We believe that this 5'-UTR G-quadruplex could be involved in regulating MECP2 translation. We mapped additional evolutionarily conserved G-quadruplexes, microRNA target sites, and AU-rich elements in the key sections of both untranslated regions. Our studies suggest the regulation of translation, mRNA turnover, and development-related alternative MECP2 polyadenylation, putatively involving interactions of conserved cis-regulatory elements with their respective trans factors and complex interactions among the trans factors themselves. We discovered highly conserved G-quadruplex motifs that were more prevalent near alternative splice sites as compared to the constitutive sites of the MECP2 gene. We also identified a pair of overlapping G-quadruplexes at an alternative 5' splice site that could potentially regulate alternative splicing in a negative as well as a positive way in the MECP2 pre-mRNAs.

Conclusions: A Rett syndrome mutation with decreased protein expression was found to be associated with a conserved G-quadruplex. Our studies suggest that MECP2 post-transcriptional gene expression could be regulated by several evolutionarily conserved cis-elements like G-quadruplex motifs, microRNA target sites, and AU-rich elements. This phylogenetic analysis has provided some interesting and valuable insights into the regulation of the MECP2 gene involved in autism.

MeSH terms

  • 5' Untranslated Regions
  • Alternative Splicing
  • Animals
  • Autistic Disorder / genetics*
  • Base Sequence
  • Chromosome Mapping
  • Dogs
  • Evolution, Molecular
  • G-Quadruplexes
  • Gene Deletion
  • Gene Expression Regulation*
  • Humans
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Molecular Sequence Data
  • Phylogeny
  • Polyadenylation
  • Protein Processing, Post-Translational / genetics*
  • RNA Splice Sites
  • Rats
  • Rett Syndrome / genetics


  • 5' Untranslated Regions
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • MicroRNAs
  • RNA Splice Sites