Induced DNA demethylation can reshape chromatin topology at the IGF2-H19 locus

Yoko Ito, Raffaella Nativio, Adele Murrell

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Choriocarcinomas are embryonal tumours with loss of imprinting and hypermethylation at the insulin-like growth factor 2 (IGF2)-H19 locus. The DNA methyltransferase inhibitor, 5-Aza-2'deoxycytidine (5-AzaCdR) is an approved epigenetic cancer therapy. However, it is not known to what extent 5-AzaCdR influences other epigenetic marks. In this study, we set out to determine whether 5-AzaCdR treatment can reprogram the epigenomic organization of the IGF2-H19 locus in a choriocarcinoma cancer cell line (JEG3). We found that localized DNA demethylation at the H19 imprinting control region (ICR) induced by 5-AzaCdR, reduced IGF2, increased H19 expression, increased CTCF and cohesin recruitment and changed histone modifications. Furthermore chromatin accessibility was increased locus-wide and chromatin looping topography was altered such that a CTCF site downstream of the H19 enhancers switched its association with the CTCF site upstream of the IGF2 promoters to associate with the ICR. We identified a stable chromatin looping domain, which forms independently of DNA methylation. This domain contains the IGF2 gene and is marked by a histone H3 lysine 27 trimethylation block between CTCF site upstream of the IGF2 promoters and the Centrally Conserved Domain upstream of the ICR. Together, these data provide new insights into the responsiveness of chromatin topography to DNA methylation changes.
Original languageEnglish
Pages (from-to)5290-302
Number of pages13
JournalNucleic Acids Research
Volume41
Issue number10
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Azacitidine
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA Methylation
  • Down-Regulation
  • Enhancer Elements, Genetic
  • Enzyme Inhibitors
  • Gene Expression
  • Genetic Loci
  • Genomic Imprinting
  • Histones
  • Humans
  • Insulin-Like Growth Factor II
  • Methylation
  • Mucoproteins
  • Nucleosomes
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic
  • RNA, Long Noncoding
  • Repressor Proteins

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