A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition

Genes Dev. 2008 Mar 15;22(6):756-69. doi: 10.1101/gad.455708.


Expression of Snail1 in epithelial cells triggers an epithelial-mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large intron located in its 5'-untranslated region (UTR). This intron contains an internal ribosome entry site (IRES) necessary for the expression of Zeb2. Maintenance of 5'-UTR Zeb2 intron is dependent on the expression of a natural antisense transcript (NAT) that overlaps the 5' splice site in the intron. Ectopic overexpression of this NAT in epithelial cells prevents splicing of the Zeb2 5'-UTR, increases the levels of Zeb2 protein, and consequently down-regulates E-cadherin mRNA and protein. The relevance of these results is demonstrated by the strong association between NAT presence and conservation of the 5'-UTR intron in cells that have undergone EMT or in human tumors with low E-cadherin expression. Therefore, the results presented in this article reveal the existence of a NAT capable of activating Zeb2 expression, explain the mechanism involved in this activation, and demonstrate that this NAT regulates E-cadherin expression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Blotting, Western
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Case-Control Studies
  • Cell Line
  • Cells, Cultured
  • Colon
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • DNA Primers
  • Epithelium / physiology*
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Mesoderm / physiology*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Plasmids
  • Promoter Regions, Genetic
  • RNA, Antisense / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Fingers


  • 5' Untranslated Regions
  • Cadherins
  • DNA Primers
  • GEMIN2 protein, human
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • RNA, Antisense
  • RNA, Messenger
  • RNA-Binding Proteins
  • Repressor Proteins
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2