PMID- 20921386 OWN - NLM STAT- MEDLINE DCOM- 20101122 LR - 20211020 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 107 IP - 42 DP - 2010 Oct 19 TI - Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. PG - 18161-6 LID - 10.1073/pnas.1005595107 [doi] AB - 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. FAU - Wu, Hao AU - Wu H AD - Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA. haowu7@gmail.com FAU - Tao, Jifang AU - Tao J FAU - Chen, Pauline J AU - Chen PJ FAU - Shahab, Atif AU - Shahab A FAU - Ge, Weihong AU - Ge W FAU - Hart, Ronald P AU - Hart RP FAU - Ruan, Xiaoan AU - Ruan X FAU - Ruan, Yijun AU - Ruan Y FAU - Sun, Yi E AU - Sun YE LA - eng SI - GEO/GSE24329 GR - RC1 CA147187/CA/NCI NIH HHS/United States GR - R03 DA022262-01/DA/NIDA NIH HHS/United States GR - R21 MH085088/MH/NIMH NIH HHS/United States GR - R21 MH085088-02/MH/NIMH NIH HHS/United States GR - R01 MH048095/MH/NIMH NIH HHS/United States GR - R18 MH048095/MH/NIMH NIH HHS/United States GR - R03 DA022262/DA/NIDA NIH HHS/United States GR - RC1 CA147187-01/CA/NCI NIH HHS/United States GR - R21 MH085088-01A1/MH/NIMH NIH HHS/United States GR - R56 MH082068/MH/NIMH NIH HHS/United States GR - R56MH082068/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20101004 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (3' Untranslated Regions) RN - 0 (Mecp2 protein, mouse) RN - 0 (Methyl-CpG-Binding Protein 2) RN - 0 (MicroRNAs) SB - IM MH - 3' Untranslated Regions MH - Animals MH - Chromatin Immunoprecipitation MH - *Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay MH - *Genome-Wide Association Study MH - Methyl-CpG-Binding Protein 2/genetics/*physiology MH - Mice MH - Mice, Knockout MH - MicroRNAs/*genetics MH - Promoter Regions, Genetic MH - Rett Syndrome/*genetics/metabolism PMC - PMC2964235 COIS- The authors declare no conflict of interest. EDAT- 2010/10/06 06:00 MHDA- 2010/12/14 06:00 PMCR- 2011/04/19 CRDT- 2010/10/06 06:00 PHST- 2010/10/06 06:00 [entrez] PHST- 2010/10/06 06:00 [pubmed] PHST- 2010/12/14 06:00 [medline] PHST- 2011/04/19 00:00 [pmc-release] AID - 1005595107 [pii] AID - 201005595 [pii] AID - 10.1073/pnas.1005595107 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18161-6. doi: 10.1073/pnas.1005595107. Epub 2010 Oct 4.