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

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...

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Autores principales: Bagga, Joetsaroop S, D’Antonio, Lawrence A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844687/
https://www.ncbi.nlm.nih.gov/pubmed/24040966
http://dx.doi.org/10.1186/1479-7364-7-19
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author Bagga, Joetsaroop S
D’Antonio, Lawrence A
author_facet Bagga, Joetsaroop S
D’Antonio, Lawrence A
author_sort Bagga, Joetsaroop S
collection PubMed
description 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.
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spelling pubmed-38446872013-12-06 Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism Bagga, Joetsaroop S D’Antonio, Lawrence A Hum Genomics Primary Research 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. BioMed Central 2013-09-16 /pmc/articles/PMC3844687/ /pubmed/24040966 http://dx.doi.org/10.1186/1479-7364-7-19 Text en Copyright © 2013 Bagga and D'Antonio; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Primary Research
Bagga, Joetsaroop S
D’Antonio, Lawrence A
Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title_full Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title_fullStr Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title_full_unstemmed Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title_short Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
title_sort role of conserved cis-regulatory elements in the post-transcriptional regulation of the human mecp2 gene involved in autism
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844687/
https://www.ncbi.nlm.nih.gov/pubmed/24040966
http://dx.doi.org/10.1186/1479-7364-7-19
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