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bioRxiv · 10.1101/2022.09.18.508380

TransCistor reveals the landscape of cis-regulatory long noncoding RNAs

Chouvardas, P.·Zimmerli, M.·Hanhart, D.·Moser, M.·Guillen-Ramirez, H. A.·Mishra, S.·Esposito, R.·Polidori, T.·Widmer, M.·Garcia-Perez, R.·Kruithof-de Julio, M.·Pervouchine, D. D.·Mele, M.·Johnson, R.
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Abstract

A key attribute of some long noncoding RNAs (lncRNAs) is their ability to regulate expression of neighbouring genes in cis. However, such cis-lncRNAs are presently defined using ad hoc criteria that, we show, are prone to false-positive predictions. The resulting lack of cis-lncRNA catalogues hinders our understanding of their extent, characteristics and mechanisms. Here, we introduce TransCistor, a framework for defining and identifying cis-lncRNAs based on enrichment of targets amongst proximal genes. TransCistors simple and conservative statistical models are compatible with functionally-defined target gene maps generated by existing and future technologies. Using transcriptome-wide perturbation experiments for 268 human and 134 mouse lncRNAs, we provide the first large-scale survey of cis-lncRNAs. Known cis-lncRNAs are correctly identified, including XIST, LINC00240 and UMLILO, and predictions are consistent across analysis methods, perturbation types and independent experiments. Our results indicate that cis-activity is detected in a minority of lncRNAs, primarily involving activators over repressors. Cis-lncRNAs are detected by both RNA interference and antisense oligonucleotide perturbations. Mechanistically, cis-lncRNA transcripts are observed to physically associate with their target-genes, and are weakly enriched with enhancer-elements. In summary, TransCistor establishes a quantitative foundation for cis-lncRNAs, opening a path to elucidating their molecular mechanisms and biological significance.

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Chouvardas, P., Zimmerli, M., Hanhart, D., Moser, M., Guillen-Ramirez, H. A., Mishra, S., Esposito, R., Polidori, T., Widmer, M., Garcia-Perez, R., Kruithof-de Julio, M., Pervouchine, D. D., Mele, M., Johnson, R.. 2022-09-19. TransCistor reveals the landscape of cis-regulatory long noncoding RNAs. https://doi.org/10.1101/2022.09.18.508380

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