Uncovering functional lncRNAs by scRNA-seq with ELATUS

Long non-coding RNAs (lncRNAs) play fundamental roles in cellular processes and pathologies, regulating gene expression at multiple levels. Despite being highly cell type-specific, their study at single-cell (sc) level has been challenging due to their less accurate annotation and low expression compared to protein-coding genes. To identify the important, albeit widely overlooked, specific lncRNAs from scRNA-seq data, here, we develop a computational framework, ELATUS, based on the pseudoaligner Kallisto that enhances the detection of functional lncRNAs previously undetected and exhibits higher concordance with the ATAC-seq profiles in single-cell multiome data. Importantly, we then independently confirmed the expression patterns of cell type-specific lncRNAs exclusively detected with ELATUS and unveiled biologically important lncRNAs, such as AL121895.1, a previously undocumented cis-repressor lncRNA, whose role in breast cancer progression was unnoticed by traditional methodologies. Our results emphasize the necessity for an alternative scRNA-seq workflow tailored to lncRNAs that sheds light on the multifaceted roles of lncRNAs.