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Induction of DNA methylation and gene silencing by short interfering RNAs in human cells

Author

Listed:
  • Hiroaki Kawasaki

    (The University of Tokyo
    National Institute of Advanced Industrial Science and Technology (AIST))

  • Kazunari Taira

    (The University of Tokyo
    National Institute of Advanced Industrial Science and Technology (AIST))

Abstract

Double-stranded RNAs (dsRNAs) induce post-transcriptional gene silencing in several species of animal and plant1,2. In plants, dsRNAs targeted to CpG islands within a promoter can also induce RNA-directed DNA methylation3,4,5,6,7,8; however, it remains unclear whether gene silencing mediated by DNA methylation can be induced by dsRNAs in mammalian cells. Here, we demonstrate that short interfering RNAs (siRNAs; 21–25-nucleotide RNA molecules) induce DNA methylation and histone H3 methylation in human cells. Synthetic siRNAs targeted to CpG islands of an E-cadherin promoter induced significant DNA methylation and histone H3 lysine 9 methylation in both MCF-7 and normal mammary epithelial cells. As a result, these siRNAs repressed expression of the E-cadherin gene at the transcriptional level. In addition, disrupting the expression of either one of two DNA methyltransferases (DNMT1 or DNMT3B) by specific siRNAs abolished the siRNA-mediated methylation of DNA. Moreover, vector-based siRNAs targeted to the erbB2 (also known as HER2) promoter also induced DNA methylation in MCF-7 cells. Thus, siRNAs targeted to CpG islands within the promoter of a specific gene can induce transcriptional gene silencing by means of DNA-methyltransferase-dependent methylation of DNA in human cells, and might have potential as a new type of gene therapeutic agent.

Suggested Citation

  • Hiroaki Kawasaki & Kazunari Taira, 2004. "Induction of DNA methylation and gene silencing by short interfering RNAs in human cells," Nature, Nature, vol. 431(7005), pages 211-217, September.
    • Handle: RePEc:nat:nature:v:431:y:2004:i:7005:d:10.1038_nature02889
    DOI: 10.1038/nature02889
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