Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
TLDR
The 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.Abstract:
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. 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. 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.read more
Citations
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Rett syndrome and MeCP2
TL;DR: A synopsis of Rett syndrome as a severe neurological disorder and the role of MeCP2 in RTT pathophysiology is discussed, which highlights the importance of understanding the molecular mechanisms by which Me CP2 impacts brain development, mental conditions, and compromised brain function.
Journal ArticleDOI
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome
Kamal K.E. Gadalla,Kamal K.E. Gadalla,Thishnapha Vudhironarit,Ralph D. Hector,Sarah E. Sinnett,Noha Gamal Bahey,Noha Gamal Bahey,Mark E.S. Bailey,Steven J. Gray,Stuart Cobb +9 more
TL;DR: The results show that controlling levels of MeCP2 expression in the liver is achievable through modification of the expression cassette, and highlights the importance of achieving high brain transduction to impact the RTT-like phenotypes.
Journal ArticleDOI
QGRS-Conserve: a computational method for discovering evolutionarily conserved G-quadruplex motifs
TL;DR: The QGRS-Conserve method quantitatively evaluates conservation between quadruplexes found in homologous nucleotide sequences based on several motif structural characteristics and efficiently manages overlapping G-quadruplex sequences such that the resulting datasets can be analyzed effectively.
Journal ArticleDOI
FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype.
Jason Arsenault,Shervin Gholizadeh,Yosuke Niibori,Laura K. K. Pacey,Sebok Kumar Halder,Enea Koxhioni,Ayumu Konno,Hirokazu Hirai,David R. Hampson +8 more
TL;DR: A wide range of neuronal F MRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP.
Journal ArticleDOI
Enhancer-promoter interaction facilitated by transiently forming G-quadruplexes
TL;DR: It is shown that DNAse hypersensitive (DHS) cis-regulatory elements are also enriched in Gs and their G-content correlate with that of their respective promoters, each contributing half a G4.
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