Transcriptional Inhibiton of Hoxd4 Expression by miRNA-10a in Human Breast Cancer Cells

BMC Mol Biol. 2009 Feb 22;10:12. doi: 10.1186/1471-2199-10-12.

Abstract

Background: Small noncoding RNAs (ncRNAs), including short interfering RNAs (siRNAs) and microRNAs (miRNAs), can silence genes at the transcriptional, post-transcriptional or translational level 12.

Results: Here, we show that microRNA-10a (miR-10a) targets a homologous DNA region in the promoter region of the hoxd4 gene and represses its expression at the transcriptional level. Mutational analysis of the miR-10a sequence revealed that the 3' end of the miRNA sequence is the most critical element for the silencing effect. MicroRNA-10a-induced transcriptional gene inhibition requires the presence of Dicer and Argonautes 1 and 3, and it is related to promoter associated noncoding RNAs. Bisulfite sequencing analysis showed that the reduced hoxd4 expression was accompanied by de novo DNA methylation at the hoxd4 promoter. We further demonstrated that trimethylation of histone 3 lysine 27 (H3K27me3) is involved in the miR-10a-induced hoxd4 transcriptional gene silence.

Conclusion: In conclusion, our results demonstrate that miR-10a can regulate human gene expression in a transcriptional manner, and indicate that endogenous small noncoding RNA-induced control of transcription may be a potential system for expressional regulation in human breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argonaute Proteins
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA Methylation
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factors / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • HeLa Cells
  • Homeodomain Proteins / metabolism*
  • Humans
  • MicroRNAs / metabolism*
  • Promoter Regions, Genetic
  • Ribonuclease III / metabolism

Substances

  • AGO1 protein, human
  • AGO3 protein, human
  • Argonaute Proteins
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factors
  • HOXD1 protein, human
  • Homeodomain Proteins
  • MicroRNAs
  • Ribonuclease III