In addition to directly affecting the expression of genes and miRNAs by direct binding to promoter regions, changes in MYCN levels undoubtedly also cause a cascade of secondary alterations to the transcriptome. Genome-wide analysis of MYCN binding has also established a more global role for MYCN as a 179324-69-7 mediator of chromatin structure . Consistent with this concept, we recently reported the association of MYCN to regions of DNA hypermethylation, through the integration of chromatin immunoprecipitation on chip and methylated DNA immunoprecipitation on chip data . The aberrant hypermethylation of gene promoters is a well known mechanism for the transcriptional silencing of tumor suppressor genes in many forms of cancer including neuroblastoma . We hypothesized that the association between MYCN binding and regions of DNA hypermethylation may be due to the action of an intermediate methyl binding protein . Of the MBD proteins, MeCP2 is essential in human brain development and has been linked to several cancer types and neurodevelopmental disorders . MeCP2 can selectively bind to methylated CpG residues, has been shown to localize to inactive heterochromatic regions of DNA, and interacts with the transcriptional repressor SIN3A to recruit histone deacetylases to repress transcription of methylated promoters . However, this classic model of MeCP2 as a transcriptional repressor has been called into question, as methylated and imprinted genes remain silent in MeCP2-deficient mice and gene expression profiling experiments failed to identify MeCP2 target genes regulated by methylated promoters . A genomewide study of MeCP2 binding sites revealed that a large percentage of MeCP2-bound gene promoters were unmethylated and actively transcribed . This result was supported by Charhour et al. in a study showing the interaction of MeCP2 with the transcriptional activator CREB1 at active promoters. Additionally, a new model of MeCP2 function proposes that MeCP2 can act as a transcriptional modulator, regulating chromatin structure at distal methylation sites to modulate the expression of active genes . In this study, we have carried out genome-wide analysis of MYCN and MeCP2 binding sites in combination with methylation analysis, and have characterized a novel co-occupancy of these SP600125 JNK inhibitor proteins at promoter regions. Gene expression analysis of bound promoters reveals differential expression levels of genes bound individually by, or in combination with MYCN and MeCP2. Taken together, our results suggest that the majority of hypermethylated MYCN sites are also bound by the methyl binding protein MeCP2, that a greater number of MYCN/ MeCP2 positive sites occur outside of hypermethylated loci and points to a role for MeCP2 in the modulation of gene expression in MYCN amplified tumors.