Functional identification of cis-regulatory long noncoding RNAs at controlled false-discovery rates

Abstract

Long noncoding RNAs (lncRNAs) can positively and negatively regulate expression of target genes encoded in cis. However, the extent, characteristics and mechanisms of such cis-regulatory lncRNAs (cis-lncRNAs) remain obscure. Until now, they have been defined using inconsistent, ad hoc criteria that can result in false-positive predictions. Here, we introduce TransCistor, a framework for defining and identifying cis-lncRNAs based on enrichment of targets amongst proximal genes. Using transcriptome-wide perturbation experiments for 190 human and 133 mouse lncRNAs, we provide the first large-scale view of cis-lncRNAs. Our results ascribe cis-regulatory activity to only a small fraction (~10%) of lncRNAs, with a prevalence of activators over repressors. Cis-lncRNAs are detected at similar rates by both RNA interference (RNAi) and antisense oligonucleotide (ASO) perturbations. We employ histone modification and chromatin folding analyses to evaluate mechanistic models for cis-lncRNAs. Thus, TransCistor places cis-regulatory lncRNAs on a quantitative foundation for the first time.

Syntenic lncRNAs exhibit DNA regulatory functions with sequence evolution

“…Previous studies have shown that multiple lncRNA which were in proximity to neighboring protein-coding genes were known to be cis- regulating their expression (Gil & Ulitsky, 2020). This cis-regulation was either due to the escorting of TFs to the regulatory regions by the RNA molecules or the presence of DNA regulatory elements on the lncRNA loci (Yap et al, 2010; Schertzer et al, 2019; Chouvardas et al, 2022; Winkler et al, 2022). This compelled us to also look into whether the syntenic lncRNA exhibits a cis-regulatory signature that governs the expression of the neighboring genes.…”