1584-P: An Integrative Transcriptome Subtraction Strategy to Identify Human LncRNAs That Specifically Play a Role in Liver Fibrosis

Liver fibrosis constitutes the most prominent predictor of overall mortality in non-alcoholic steatohepatitis. The fibrotic liver features excessive deposition of extracellular matrix, primarily produced from "activated" hepatic stellate cells (HSCs). Whereas targeting HSC in fibrosis therapeutics shows promise, the overall understanding of HSC activation remains limited, partly because defining the role of human long non-coding RNAs (lncRNAs) in HSC activation remains challenging. Although analyzing regulated human lncRNAs by HSC activation provides the most practical means to identify functional lncRNAs in the process, effective downstream approaches to further prioritize the regulated lncRNAs are often lacking. To address this challenge, we conceptualize that profibrogenic human lncRNAs in HSCs could be specifically identified by concurrent analysis of regulated lncRNAs during HSC activation with those in a process under which diverse gene networks are regulated, but the molecular elements of fibrogenesis are the only shared one with HSC activation. To implement this strategy, we compared those genes with TGFbeta-regulated ones in four additional cell types and found that only TGFbeta-induced transdifferentiation of vascular smooth muscle cells share the key elements of fibrogenesis with HSC activation. We utilized this approach to identify a highly filtered list of lncRNA candidates, and experimentally characterized and validated one fibrogenic human lncRNA named CARMN. Our work addresses a bottleneck in identifying human lncRNAs that specifically play a role in HSC activation and liver fibrosis through integrative transcriptome subtractions, and our study provides a framework to effectively select human lncRNAs that are essential for elucidating key pathological processes.