XIST and miRNA sequestration: Insights into lncRNA-mediated gene regulation


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Erin A Marshall1,Greg L Stewart1,Adam P Sage1,Wan L Lam1,Carolyn J Brown2
1BC Cancer Research Centre,2University of British Columbia

Abstract

Background

An emerging mechanism of long non-coding RNA-mediated regulation is through “sponging” of miRNAs, in which lncRNA promote the upregulation of canonical miRNA-target genes. XIST is a well-studied lncRNA involved in cis-silencing of an X chromosome in females, but existing studies considering one miRNA and XIST expression in singular cancer types do not account for important biological considerations including sex and localization of transcripts. Here, we use the sex-specificity of XIST to detail a biology-driven pipeline for the discovery of candidate miRNA and gene targets in lncRNA sponging, and validate the miRNA that may be mediating these interactions in XIST.

Method

To find genes regulated by XIST-mediated miRNA sponging, we correlated all Ensembl-annotated genes with XIST expression in female lung adenocarcinoma (LUAD, n=307; rho>0.4, p<0.05). Using an algorithm based on binding energies and sequence homology, we assessed the binding of all miRNAs against target genes and XIST. We then determine the best candidates using XIST-high (female/male) and XIST-low (male) systems, and validate the presence of these candidate miRNAs in the nucleus by RT-qPCR.

Results

We find 543 genes that may be defended from miRNAs by XIST (DMX genes), with a predicted 804 miRNAs targeting both DMX genes and XIST. We compared the changes in miRNA-DMX relationships in XIST-high and XIST-low systems and identified a high-confidence set of 13 miRNA-DMX gene pairs.

Conclusion

Recent publications of numerous lncRNA sponging studies are mostly limited in biological context. By analyzing the transcriptome of female and male LUAD and in the context of sex-specificity, we reveal the best miRNA targets in the XIST-miRNA-DMX gene sponging axis. Importantly, we find these miRNAs are enriched in the nucleus, co-localizing with XIST. Our analysis provides both a comprehensive methodology for studying cancer-related miRNA sponges and suggests the relevance of lncRNA sponging to gene expression regulation in cancer.