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Human Molecular Genetics Advance Access published online on May 8, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl124
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received March 20, 2006
Revised May 3, 2006
Accepted May 3, 2006

Article

Inhibitors of Differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome

Sailaja Peddada 1, Dag H. Yasui 1, and Janine M. LaSalle 1 *

1 Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, One Shields Ave, University of California, Davis, CA, 95616, USA

* To whom correspondence should be addressed.
Janine M. LaSalle, E-mail: jmlasalle{at}ucdavis.edu


  Abstract

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix (HLH) genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT.


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