Genome-wide analysis reveals methyl-CpG–binding protein 2–dependent regulation of microRNAs in a mouse model of Rett syndrome
| Autor: | Ronald P. Hart, Hao Wu, Weihong Ge, Yijun Ruan, Xiaoan Ruan, Jifang Tao, Yi E. Sun, Atif Shahab, Pauline J. Chen |
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| Rok vydání: | 2010 |
| Předmět: |
Chromatin Immunoprecipitation
congenital hereditary and neonatal diseases and abnormalities Methyl-CpG-Binding Protein 2 Enzyme-Linked Immunosorbent Assay Rett syndrome Biology MECP2 Mice Gene expression microRNA Rett Syndrome medicine Transcriptional regulation Animals Promoter Regions Genetic 3' Untranslated Regions Gene Mice Knockout Genetics Multidisciplinary Three prime untranslated region Biological Sciences medicine.disease Disease Models Animal MicroRNAs DNA methylation Genome-Wide Association Study |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:18161-18166 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as posttranscriptional regulators of gene expression. Many miRNAs are expressed in the developing brain and regulate multiple aspects of neural development, including neurogenesis, dendritogenesis, and synapse formation. Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG–binding protein 2 ( MECP2 ). Although Mecp2 is known to act as a global transcriptional regulator, miRNAs that are directly regulated by Mecp2 in the brain are not known. Using massively parallel sequencing methods, we have identified miRNAs whose expression is altered in cerebella of Mecp2 -null mice before and after the onset of severe neurological symptoms. In vivo genome-wide analyses indicate that promoter regions of a significant fraction of dysregulated miRNA transcripts, including a large polycistronic cluster of brain-specific miRNAs, are DNA-methylated and are bound directly by Mecp2. Functional analysis demonstrates that the 3′ UTR of messenger RNA encoding Brain-derived neurotrophic factor ( Bdnf ) can be targeted by multiple miRNAs aberrantly up-regulated in the absence of Mecp2. Taken together, these results suggest that dysregulation of miRNAs may contribute to RTT pathoetiology and also may provide a valuable resource for further investigations of the role of miRNAs in RTT. |
| Databáze: | OpenAIRE |
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