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

Sailaja Peddada, Dag H. Yasui, Janine M LaSalle

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2003-2014
Number of pages12
JournalHuman Molecular Genetics
Volume15
Issue number12
DOIs
StatePublished - Jun 15 2006

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Rett Syndrome
Genes
Brain
Methyl-CpG-Binding Protein 2
Chromatin Immunoprecipitation
Microarray Analysis
Oligonucleotides
Fluorescent Antibody Technique
Cell Differentiation
Lasers
Genome
Neurons
Polymerase Chain Reaction
Mutation
DNA
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. / Peddada, Sailaja; Yasui, Dag H.; LaSalle, Janine M.

In: Human Molecular Genetics, Vol. 15, No. 12, 15.06.2006, p. 2003-2014.

Research output: Contribution to journalArticle

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