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    Global MYCN transcription factor binding analysis in neuroblastoma reveals association with distinct E-box motifs and regions of DNA hypermethylation.

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    Authors
    Murphy, Derek M
    Buckley, Patrick G
    Bryan, Kenneth
    Das, Sudipto
    Alcock, Leah
    Foley, Niamh H
    Prenter, Suzanne
    Bray, Isabella
    Watters, Karen M
    Higgins, Desmond
    Stallings, Raymond L
    Show allShow less
    Affiliation
    Department of Cancer Genetics, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Issue Date
    2009
    MeSH
    Binding Sites
    Cell Line, Tumor
    Chromatin Immunoprecipitation
    DNA Methylation
    DNA, Intergenic
    E-Box Elements
    Genetic Loci
    Humans
    MicroRNAs
    Neuroblastoma
    Nuclear Proteins
    Oncogene Proteins
    Promoter Regions, Genetic
    Protein Binding
    Transcription Factors
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    Citation
    Global MYCN transcription factor binding analysis in neuroblastoma reveals association with distinct E-box motifs and regions of DNA hypermethylation. 2009, 4 (12):e8154 PLoS ONE
    Journal
    PloS one
    URI
    http://hdl.handle.net/10147/95034
    DOI
    10.1371/journal.pone.0008154
    PubMed ID
    19997598
    Abstract
    BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p<0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure.
    Language
    en
    ISSN
    1932-6203
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0008154
    Scopus Count
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