Functional Annotation of Human Long Non-Coding RNAs via Molecular Phenotyping

Long non-coding RNAs (lncRNAs) constitute the majority of transcripts in mammalian genomes and yet, their functions remain largely unknown. We systematically suppressed 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). The resulting transcriptomic profiles recapitulated the observed cellular phenotypes, yielding specific roles for over 40% of analyzed lncRNAs in regulating distinct biological pathways, transcriptional machinery, alternative promoter activity and architecture usage. Overall, combining cellular and molecular profiling provided a powerful approach to unravel the distinct functions of lncRNAs, which we highlight with specific functional roles for ZNF213-AS1 and lnc-KHDC3L-2.