Abstract
MeCP2 encodes a methyl-CpG-binding protein that plays a critical role in repressing gene expression, mutations of which lead to Rett syndrome and autism. PTEN is a critical tumor suppressor gene that is frequently mutated in human cancers and autism spectrum disorders. Various studies have shown that both MeCP2 and PTEN proteins play important roles in brain development. Here we find that MeCP2 and PTEN reciprocally regulate expression of each other via microRNAs. Knockdown of MeCP2 leads to upregulation of microRNA-137, which in turn represses expression of PTEN, thus PTEN would be down-regulated when MeCP2 is knockdown. Furthermore, we find that deletion of PTEN leads to phosphorylation of Serine 133 of CREB, then increases the expression of microRNA-132. miR-132 inhibits the expression of MeCP2 by targeting on the 3′UTR of MeCP2 mRNA. Our work shows that two critical disorders-related gene MeCP2 and PTEN reciprocally regulate expression of each other by distinct mechanisms, suggesting that rare mutations in various disorders may lead to dysregulation of other critical genes and yield unexpected consequences.
Highlights
MeCP2 belongs to a family of methyl-CpG-binding proteins that regulate gene expression by DNA methylation via recruitment of histone deacetylases[1,2]
We further found that phosphorylation of Ser-133 of cyclic AMP-response-element-binding-protein (CREB), a substrate of PTEN phosphatase, increased after knocking down PTEN led to down-regulation of MeCP2 targeted by miR-132
Our results suggest that two specific miRNAs act as intermediates in the reciprocal regulation of PTEN and MeCP2
Summary
MeCP2 belongs to a family of methyl-CpG-binding proteins that regulate gene expression by DNA methylation via recruitment of histone deacetylases[1,2]. MeCP2 is indispensable for neural development, for example regulating expression of the brain-derived neurotrophic factor (BDNF) gene[3]. The expression of miRNAs was shown to be altered in the brains of Mecp2-null mice[15,16]. Mecp[2] knockdown repressed PTEN expression and increased AKT phosphorylation. The Mecp2-mediated effect on PTEN expression occurs via a mechanism involving miR-137. We further found that phosphorylation of Ser-133 of cyclic AMP-response-element-binding-protein (CREB), a substrate of PTEN phosphatase, increased after knocking down PTEN led to down-regulation of MeCP2 targeted by miR-132. Our work revealed that the two critical genes, Mecp[2] and Pten, regulate expression of each other by microRNA targeting and yield further molecular insights for disorders-related mechanisms
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