Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer

Esteban Ballestar, Maria F. Paz, Laura Valle, Susan Wei, Mario F. Fraga, Jesus Espada, Juan Cruz Cigudosa, Tim Hui Ming Huang, Manel Esteller

Research output: Contribution to journalArticle

269 Scopus citations

Abstract

Methyl-CpG binding proteins (MBDs) mediate histone deacetylase-dependent transcriptional silencing at methylated CpG islands. Using chromatin immunoprecitation (ChIP) we have found that gene-specific profiles of MBDs exist for hypermethylated promoters of breast cancer cells, whilst a common pattern of histone modifications is shared. This unique distribution of MBDs is also characterized in chromosomes by comparative genomic hybridization of immunoprecipitated DNA and immunolocalization. Most importantly, we demonstrate that MBD association to methylated DNA serves to identify novel targets of epigenetic inactivation in human cancer. We combined the ChIP assay of MBDs with a CpG island microarray (ChIP on chip). The scenario revealed shows that, while many genes are regulated by multiple MBDs, others are associated with a single MBD. These target genes displayed methylation-associated transcriptional silencing in breast cancer cells and primary tumours. The candidates include the homeobox gene PAX6, the prolactin hormone receptor, and dipeptidylpeptidase IV among others. Our results support an essential role for MBDs in gene silencing and, when combined with genomic strategies, their potential to 'catch' new hypermethylated genes in cancer.

Original languageEnglish (US)
Pages (from-to)6335-6345
Number of pages11
JournalEMBO Journal
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2003
Externally publishedYes

Keywords

  • ChIP on chip
  • DNA methylation
  • Epigenetic inactivation
  • MBD
  • MeCP2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Ballestar, E., Paz, M. F., Valle, L., Wei, S., Fraga, M. F., Espada, J., Cigudosa, J. C., Huang, T. H. M., & Esteller, M. (2003). Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO Journal, 22(23), 6335-6345. https://doi.org/10.1093/emboj/cdg604