Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome

被引:114
作者
Urdinguio, Rocio G. [1 ]
Fernandez, Agustin F. [1 ]
Lopez-Nieva, Pilar [1 ]
Rossi, Simona [3 ]
Huertas, Dori [1 ]
Kulis, Marta [1 ]
Liu, Chang-Gong [3 ]
Croce, Carlo [4 ]
Calin, George A. [3 ]
Esteller, Manel [1 ,2 ]
机构
[1] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Lhospitalet De Llobregat, Catalonia, Spain
[2] ICREA, Barcelona, Catalonia, Spain
[3] MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX USA
[4] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
关键词
Rett syndrome; Mecp2; microRNAs; DNA methylation; chromatin; CPG-BINDING DOMAIN; TUMOR-SUPPRESSOR GENES; DNA METHYLATION; HUMAN CANCER; MESSENGER-RNAS; PCR ASSAY; PROTEINS; EPIGENETICS; ACTIVATION; MUTATIONS;
D O I
10.4161/epi.5.7.13055
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate post-transcriptional gene expression. They influence a wide range of physiological functions, including neuronal processes, and are regulated by various mechanisms, such as DNA methylation. This epigenetic mark is recognized by transcriptional regulators such as the methyl CpG binding protein Mecp2. Rett syndrome is a complex neurological disorder that has been associated with mutations in the gene coding for Mecp2. Thus, we examined the possible miRNA misregulation caused by Mecp2 absence in a mouse model of Rett syndrome. Using miRNA expression microarrays, we observed that the brain of Rett syndrome mice undergoes a disruption of the expression profiles of miRNAs. Among the significantly altered miRNAs (26%, 65 of 245), overall downregulation of these transcripts was the most common feature (71%), while the remaining 30% were upregulated. Further validation by quantitative RT-PCR demonstrated that the most commonly disrupted miRNAs were miR-146a, miR-146b, miR-130, miR-122a, miR-342 and miR-409 (downregulated) and miR-29b, miR329, miR-199b, miR-382, miR-296, miR-221 and miR-92 (upregulated). Most importantly, transfection of miR-146a in a neuroblastoma cell line caused the downregulation of IL-1 receptor-associated kinase 1 (Irak1) levels, suggesting that the identified defect of miR-146a in Rett syndrome mice brains might be responsible for the observed upregulation of Irak1 in this model of the human disease. Overall, we provide another level of molecular deregulation occurring in Rett syndrome that might be useful for understanding the disease and for designing targeted therapies.
引用
收藏
页码:656 / 663
页数:8
相关论文
共 57 条
[1]   Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 [J].
Amir, RE ;
Van den Veyver, IB ;
Wan, M ;
Tran, CQ ;
Francke, U ;
Zoghbi, HY .
NATURE GENETICS, 1999, 23 (02) :185-188
[2]   The impact of MECP2 mutations in the expression patterns of Rett syndrome patients [J].
Ballestar, E ;
Ropero, S ;
Alaminos, M ;
Armstrong, J ;
Setien, F ;
Agrelo, R ;
Fraga, MF ;
Herranz, M ;
Avila, S ;
Pineda, M ;
Monros, E ;
Esteller, M .
HUMAN GENETICS, 2005, 116 (1-2) :91-104
[3]   Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer [J].
Ballestar, E ;
Paz, MF ;
Valle, L ;
Wei, S ;
Fraga, MF ;
Espada, J ;
Cigudosa, JC ;
Huang, THM ;
Esteller, M .
EMBO JOURNAL, 2003, 22 (23) :6335-6345
[4]   Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized [J].
Bienvenu, Thierry ;
Chelly, Jamel .
NATURE REVIEWS GENETICS, 2006, 7 (06) :415-426
[5]   MicroRNA-cancer connection: The beginning of a new tale [J].
Calin, George Adrian ;
Croce, Carlo Maria .
CANCER RESEARCH, 2006, 66 (15) :7390-7394
[6]   MeCP2, a key contributor to neurological disease, activates and represses transcription [J].
Chahrour, Maria ;
Jung, Sung Yun ;
Shaw, Chad ;
Zhou, Xiaobo ;
Wong, Stephen T. C. ;
Qin, Jun ;
Zoghbi, Huda Y. .
SCIENCE, 2008, 320 (5880) :1224-1229
[7]   MicroRNAs and cancer epigenetics: a macrorevolution [J].
Davalos, Veronica ;
Esteller, Manel .
CURRENT OPINION IN ONCOLOGY, 2010, 22 (01) :35-45
[8]   Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus [J].
Davis, Tigwa H. ;
Cuellar, Trinna L. ;
Koch, Selina M. ;
Barker, Allison J. ;
Harfe, Brian D. ;
McManus, Michael T. ;
Ullian, Erik M. .
JOURNAL OF NEUROSCIENCE, 2008, 28 (17) :4322-4330
[9]   FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice [J].
Deng, Vivianne ;
Matagne, Valerie ;
Banine, Fatima ;
Frerking, Matthew ;
Ohliger, Patricia ;
Budden, Sarojini ;
Pevsner, Jonathan ;
Dissen, Gregory A. ;
Sherman, Larry S. ;
Ojeda, Sergio R. .
HUMAN MOLECULAR GENETICS, 2007, 16 (06) :640-650
[10]   The MBD protein family-Reading an epigenetic mark? [J].
Dhasarathy, Archana ;
Wade, Paul A. .
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2008, 647 (1-2) :39-43