Abstract
In this report we have analyzed the role of antisense transcription in the control of LEF1 transcription factor expression. A natural antisense transcript (NAT) is transcribed from a promoter present in the first intron of LEF1 gene and undergoes splicing in mesenchymal cells. Although this locus is silent in epithelial cells, and neither NAT transcript nor LEF1 mRNA are expressed, in cell lines with an intermediate epithelial-mesenchymal phenotype presenting low LEF1 expression, the NAT is synthesized and remains unprocessed. Contrarily to the spliced NAT, this unspliced NAT down-regulates the main LEF1 promoter activity and attenuates LEF1 mRNA transcription. Unspliced LEF1 NAT interacts with LEF1 promoter and facilitates PRC2 binding to the LEF1 promoter and trimethylation of lysine 27 in histone 3. Expression of the spliced form of LEF1 NAT in trans prevents the action of unspliced NAT by competing for interaction with the promoter. Thus, these results indicate that LEF1 gene expression is attenuated by an antisense non-coding RNA and that this NAT function is regulated by the balance between its spliced and unspliced forms.
Highlights
Epithelial-to-Mesenchymal Transition (EMT) is a process in which epithelial cells lose epithelial characteristics and acquire a mesenchymal phenotype [1]
Among the genes induced during EMT, the transcription factor Snail1 plays a key role in this transition since it is rapidly induced, preceding the expression of the rest of the mesenchymal genes, is required for EMT and is capable of triggering this conversion when overexpressed in epithelial cells [2,3]
In this article we have characterized a natural antisense transcript that modulates the expression of the mesenchymal-specific gene Lymphoid Enhancer Factor 1 (LEF1)
Summary
Epithelial-to-Mesenchymal Transition (EMT) is a process in which epithelial cells lose epithelial characteristics and acquire a mesenchymal phenotype [1]. This process is characterized by the down-regulation of E-cadherin, a protein with a central role in the adherens junctions, and the upregulation of mesenchymal markers, such Snail, Zeb1/2, Fibronectin, Lymphoid Enhancer Factor 1 (LEF1) and Vimentin [1,2,3] During tumor progression, this process takes place through an intermediate or ‘epithelial metastable’ phenotype, co-expressing moderate levels of epithelial and mesenchymal genes [3,4]. Among the genes induced during EMT, the transcription factor Snail plays a key role in this transition since it is rapidly induced, preceding the expression of the rest of the mesenchymal genes, is required for EMT and is capable of triggering this conversion when overexpressed in epithelial cells [2,3]. 5786 Nucleic Acids Research, 2015, Vol 43, No 12 pression by interacting with the LEF1 promoter and recruiting the Polycomb Repressive Complex 2 to the LEF1 promoter
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