Dysregulation of murine long non-coding single cell transcriptome in non-alcoholic steatohepatitis and liver fibrosis

Abstract

LncRNAs are typified by low expression, nuclear enrichment, high tissue-specificity and functional diversity, but the vast majority are uncharacterized. Here, we develop a catalog of 48,000 mouse liver-expressed lncRNAs and use to elucidate lncRNA dysregulation in high fat diet-induced non-alcoholic steatohepatitis and carbon tetrachloride-induced liver fibrosis by single cell RNA-seq. LncRNA zonation patterns across the liver lobule were discovered in five cell populations. Perturbations in lncRNA expression were common in disease-associated cell types, including non-alcoholic steatohepatitis-associated macrophages, a hallmark of fatty liver disease progression, and collagen-producing myofibroblasts, key to liver fibrosis. Gene regulatory network analysis linked individual lncRNAs to biological pathways and network centrality metrics identified network-essential, disease-associated regulatory lncRNAs. Regulatory lncRNAs with network-predicted target gene promoters enriched for triplex-based lncRNA binding were also identified. These findings elucidate hepatic lncRNA cell-type specificities, spatial zonation patterns, linked biological networks and dysregulation in disease progression. A subset of the disease-associated lncRNAs have human orthologs and are promising candidates for biomarkers and therapeutic targets.