Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome

Hao Wu, Jifang Tao, Pauline J. Chen, Atif Shahab, Weihong Ge, Ronald P. Hart, Xiaoan Ruan, Yijun Ruan, Yi E. Sun

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

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 genomewide 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 upregulated 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.

Original languageEnglish (US)
Pages (from-to)18161-18166
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number42
DOIs
StatePublished - Oct 19 2010

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Brain-derived neurotrophic factor
  • Cerebella
  • DNA methylation
  • Dlk1-Gtl2 imprinting locus
  • Massively parallel sequencing

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