DNA demethylation by 5-aza-2′-deoxycytidine is imprinted, targeted to euchromatin, and has limited transcriptional consequences

María Paz Ramos, Neil Ari Wijetunga, Andrew S. McLellan, Masako Suzuki, John M. Greally

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background: DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2′-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. Results: We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic 'imprint' of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci-encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Conclusions: Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation.

Original languageEnglish (US)
Article number11
JournalEpigenetics and Chromatin
Volume8
Issue number1
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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