Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism
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DOI：
10.1186/1479-7364-7-19
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发表时间：
2013-09-16
期刊：
影响因子：
4.5
通讯作者：
D'Antonio, Lawrence A.
中科院分区：
文献类型：
--
作者：
Bagga, Joetsaroop S.;D'Antonio, Lawrence A.
背景：MECP2基因编码甲基CpG结合蛋白2，该蛋白在大脑早期发育过程中调控其他基因的活性。该基因的突变与Rett综合征（一种自闭症）有关。本研究的目的是研究进化上保守的顺式元件在调节MECP2基因转录后表达中的作用，并探讨它们与已知导致智力迟钝的突变的可能相关性。结果：利用生物信息学方法绘制了人类MECP2基因转录区及其哺乳动物同源基因中进化保守的顺式调控元件。顺式调控基序包括g -四联体、microRNA靶点和富au元素，它们在关键的生物过程和治疗靶点中发挥着重要作用。我们在MECP2 mRNA的5'-UTR（非翻译区）发现了一个高度保守的g -四重体，它与Rett综合征患者中MECP2蛋白水平降低的已知缺失重叠。我们认为这个5'-UTR g -四重体可能参与调节MECP2的翻译。我们在两个非翻译区域的关键部分绘制了其他进化上保守的g -四联体、microRNA靶点和富au元素。我们的研究表明，翻译、mRNA转换和与发育相关的MECP2多聚腺苷化的调控可能涉及保守的顺式调控元件与其各自的反式因子的相互作用以及反式因子之间的复杂相互作用。我们发现与MECP2基因的组成位点相比，高度保守的g -四重基序在替代剪接位点附近更为普遍。我们还在另一个5'剪接位点发现了一对重叠的g -四联体，它们可能以阴性和阳性的方式调节MECP2 pre- mrna的选择性剪接。结论：Rett综合征突变与蛋白表达降低与保守的g -四重体有关。我们的研究表明，MECP2转录后基因的表达可能受到几个进化上保守的顺式元件如g -四重基序、microRNA靶点和富au元件的调控。这一系统发育分析为MECP2基因在自闭症中的调控提供了一些有趣而有价值的见解。
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.