title: Co-localization of the oncogenic transcription factor MYCN and the DNA methyl binding protein MeCP2 at genomic sites in neuroblastoma.
abstract: BACKGROUND
  MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma. MeCP2 is a CpG methyl binding protein which has been associated with a number of cancers and developmental disorders, particularly Rett syndrome.
  
  
  RESULTS
  Using an integrative global genomics approach involving chromatin immunoprecipitation applied to microarrays, we have determined that MYCN and MeCP2 co-localize to gene promoter regions, as well as inter/intragenic sites, within the neuroblastoma genome (MYCN amplified Kelly cells) at high frequency (70.2% of MYCN sites were also positive for MeCP2). Intriguingly, the frequency of co-localization was significantly less at promoter regions exhibiting substantial hypermethylation (8.7%), as determined by methylated DNA immunoprecipitation (MeDIP) applied to the same microarrays. Co-immunoprecipitation of MYCN using an anti-MeCP2 antibody indicated that a MYCN/MeCP2 interaction occurs at protein level. mRNA expression profiling revealed that the median expression of genes with promoters bound by MYCN was significantly higher than for genes bound by MeCP2, and that genes bound by both proteins had intermediate expression. Pathway analysis was carried out for genes bound by MYCN, MeCP2 or MYCN/MeCP2, revealing higher order functions.
  
  
  CONCLUSIONS
  Our results indicate that MYCN and MeCP2 protein interact and co-localize to similar genomic sites at very high frequency, and that the patterns of binding of these proteins can be associated with significant differences in transcriptional activity. Although it is not yet known if this interaction contributes to neuroblastoma disease pathogenesis, it is intriguing that the interaction occurs at the promoter regions of several genes important for the development of neuroblastoma, including ALK, AURKA and BDNF.
authors: Department of Cancer Genetics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: Derek M
authors: DM
authors: Murphy
authors: Patrick G
authors: PG
authors: Buckley
authors: Sudipto
authors: S
authors: Das
authors: Karen M
authors: KM
authors: Watters
authors: Kenneth
authors: K
authors: Bryan
authors: Raymond L
authors: RL
authors: Stallings
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D019295:Computational Biology; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D024721:E-Box Elements / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D057898:Hemizygote; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; C459801:MYCN protein, human; D051783:Methyl-CpG-Binding Protein 2; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; D004247:DNA