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

Yoko Ito1, Raffaella Nativio, Adele Murrell

  • 1Department of Oncology, University of Cambridge, CRUK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.

Nucleic Acids Research
|April 16, 2013
PubMed

Insights

5-Aza-2'deoxycytidine (5-AzaCdR) epigenetic therapy reprogrammed the IGF2-H19 locus in choriocarcinoma cells. This DNA demethylation altered gene expression, protein binding, and chromatin looping, revealing insights into epigenomic organization.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genomics

Background:

  • Choriocarcinomas exhibit epigenetic alterations at the IGF2-H19 locus, including hypermethylation.
  • 5-Aza-2'deoxycytidine (5-AzaCdR) is an approved epigenetic cancer therapy targeting DNA methylation.

Purpose of the Study:

  • To investigate the impact of 5-AzaCdR on the epigenomic organization of the IGF2-H19 locus in choriocarcinoma cells.
  • To determine if 5-AzaCdR can reprogram the epigenetic landscape of this critical cancer-related locus.

Main Methods:

  • Utilized JEG3 choriocarcinoma cell line for treatment with 5-AzaCdR.
  • Analyzed DNA methylation, gene expression (IGF2, H19), protein recruitment (CTCF, cohesin), histone modifications, and chromatin accessibility.
  • Performed chromatin looping analysis to assess structural changes.

Main Results:

  • 5-AzaCdR induced localized DNA demethylation at the H19 imprinting control region (ICR).
  • Treatment led to reduced IGF2 and increased H19 expression, altered CTCF and cohesin binding, and modified histone marks.
  • Chromatin accessibility increased locus-wide, and looping topography shifted, with a downstream CTCF site associating with the ICR.
  • A stable, methylation-independent chromatin loop containing the IGF2 gene was identified, marked by H3K27 trimethylation.

Conclusions:

  • 5-AzaCdR effectively reprograms the epigenomic organization of the IGF2-H19 locus in choriocarcinoma.
  • DNA methylation changes induced by 5-AzaCdR significantly influence chromatin accessibility, looping, and gene expression.
  • Findings provide novel insights into the dynamic interplay between DNA methylation and higher-order chromatin structure in cancer epigenetics.

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