title: Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism.
abstract: 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.
authors.affiliation: Ramapo College of New Jersey, 505 Ramapo Valley Rd,, Mahwah, NJ 07430, USA. ldant@ramapo.edu.
authors.forename: Joetsaroop S
authors.initials: JS
authors.lastname: Bagga
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: D'Antonio
mesh_terms: D020121:5' Untranslated Regions; D017398:Alternative Splicing; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D004285:Dogs; D019143:Evolution, Molecular; D054856:G-Quadruplexes; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D026723:Polyadenylation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D022821:RNA Splice Sites; D051381:Rats; D015518:Rett Syndrome / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D022821:RNA Splice Sites
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