A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition.
By M. Beltran, I. Puig, C. Peña, J. García, Ana Belén Álvarez, R. Peña, F. Bonilla, A. G. de Herreros. Genes & Development, 2008
667 citations recorded by the source corpus.
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.
Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/bc0bcc037896bae2c22c8c9f8711625c8bb7eb83
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In Cardiology and Cardiovascular Medicine
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Citations in the corpus
- Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, background): “For instance, natural antisense transcripts (NATs) influence splicing patterns from the neuroblastoma MYC intron 1 splicing which is the sense encoded gene (17).”
- The rise of regulatory RNA (2014, background): “Some lncRNAs, similar to small ncRNAs 258 , have been shown to control alternative splicing 259,260 .”
- Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits (2009, background): “46 ); a similar role has been associated with a natural anti-sense transcript transcribed from the ZEB2 locu”
- Long Noncoding RNAs: Past, Present, and Future (2013, neutral): “…the mRNAs opposite them in vivo and/or inhibit splicing in vitro, led to speculation that NAT-mediated alternative splicing may be a common method of post-transcriptional regulation (Munroe 1988; Krystal et al. 1990; Khochbin et al. 1992; Yan et al. 2005; Beltran et al. 2008; Annilo et al. 2009).”
- Long noncoding RNAs: functional surprises from the RNA world. (2009, background): “Upon EMT, a NAT is produced that is complementary to the 59 splice site of this intron, thus blocking the spliceosome from removing the IRES from the mature mRNA and enabling expression of the Zeb2/ Sip1 protein (Beltran et al. 2008).”
- The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “For example, Snail1 increases Zeb2 expression by a complex mechanism that involves the regulation of a natural Zeb2 antisense transcript that prevents the splicing of an intron in the 5′UTR of the Zeb2 gene and increases transcript levels (Beltran et al. 2008).”
- miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA (2011, background): “…et al, 2008), (ii) stabilization of mRNA by duplex formation (Faghihi et al, 2008), (iii) perturbation of splicing leading to intron inclusion (Beltran et al, 2008), (iv) epigenetic silencing by deposition of silent state chromatin marks similar to TGS (Yap et al, 2010), and (v) a collision…”