Identification of an enhancer that increases miR-200b~200a~429 gene expression in breast cancer cells

PLoS One. 2013 Sep 25;8(9):e75517. doi: 10.1371/journal.pone.0075517. eCollection 2013.

Abstract

The miR-200b~200a~429 gene cluster is a key regulator of EMT and cancer metastasis, however the transcription-based mechanisms controlling its expression during this process are not well understood. We have analyzed the miR-200b~200a~429 locus for epigenetic modifications in breast epithelial and mesenchymal cell lines using chromatin immunoprecipitation assays and DNA methylation analysis. We discovered a novel enhancer located approximately 5.1kb upstream of the miR-200b~200a~429 transcriptional start site. This region was associated with the active enhancer chromatin signature comprising H3K4me1, H3K27ac, RNA polymerase II and CpG dinucleotide hypomethylation. Luciferase reporter assays revealed the upstream enhancer stimulated the transcription of the miR-200b~200a~429 minimal promoter region approximately 27-fold in breast epithelial cells. Furthermore, we found that a region of the enhancer was transcribed, producing a short, GC-rich, mainly nuclear, non-polyadenylated RNA transcript designated miR-200b eRNA. Over-expression of miR-200b eRNA had little effect on miR-200b~200a~429 promoter activity and its production did not correlate with miR-200b~200a~429 gene expression. While additional investigations of miR-200b eRNA function will be necessary, it is possible that miR-200b eRNA may be involved in the regulation of miR-200b~200a~429 gene expression and silencing. Taken together, these findings reveal the presence of a novel enhancer, which contributes to miR-200b~200a~429 transcriptional regulation in epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Chromatin / genetics
  • Enhancer Elements, Genetic / genetics*
  • Epigenomics / methods
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • MicroRNAs / genetics*
  • Promoter Regions, Genetic / genetics
  • RNA / genetics
  • Transcription Initiation Site

Substances

  • Chromatin
  • MicroRNAs
  • RNA

Grants and funding

This work was supported by a Project Grant APP1008440 from the National Health and Medical Research Council to GG and FS, and by funds from the Swedish Medical Research Council (Vetenskapsrådet, 521-2009-2873), Lund University Faculty of Medicine and The Hemato-Linne Program to JA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.