TransCistor reveals the landscape of cis-regulatory long noncoding RNAs

ABSTRACT Long noncoding RNAs (lncRNAs) are believed to regulate expression of neighbouring target genes. However, such ‘cis-lncRNAs’ are presently defined using ad hoc criteria that, we show, are prone to false-positive predictions. The resulting lack of confident 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. TransCistor’s simple and conservative statistical models are compatible with functionally-defined target gene maps generated by existing and future technologies, and generate predictions at controlled false discovery rates. Using transcriptome-wide perturbation experiments for 268 human and 134 mouse lncRNAs, we provide the first large-scale survey of cis-lncRNAs. Our results suggest that cis-activity is confined to a minority of lncRNAs, with a prevalence of activators over repressors. Cis-lncRNAs are detected by both RNA interference (RNAi) and antisense oligonucleotide (ASO) perturbations. Mechanistically, we find weak associations of cis-lncRNAs with enhancer elements. Moreover, they are not distinguished from other lncRNAs by evolutionary conservation nor nuclear enrichment, nor are they frequently linked to target genes by chromatin looping. In summary, our study will enable researchers to evaluate the regulatory mode of their lncRNA of interest at controlled false discovery rates and places cis-lncRNAs on a quantitative foundation for the first time.