Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators

To systemically identify long noncoding RNAs (lncRNAs) regulating energy metabolism, we performed transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Of 4,759 regulated lncRNAs, function-oriented filters yield 359 tissue-specifically regulated and metabolically sensitive lncRNAs that are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by nutrients, metabolic hormones, and key transcription factors were further defined in primary hepatocytes. Combining genome-wide screens, bioinformatics function predictions, and cell-based analyses, we developed an integrative roadmap to identify lncRNA metabolic regulators. An lncLMS was experimentally confirmed in mice to suppress lipogenesis by forming a negative feedback loop in the SREBP1c pathway. Taken together, this study supports that a class of lncRNAs function as important metabolic regulators and establishes a framework for systemically investigating the role of lncRNAs in physiological homeostasis. [Display omitted] •Genome-wide screens define 359 metabolically sensitive lncRNAs in key metabolic organs•LncRNA functions were predicted by mRNA-lncRNA correlation analyses•In vitro assays connect lncRNAs to specific metabolic and signaling pathways•SREBP1c induces Gm16551 to activate an lncRNA-mediated negative feedback loop Yang et al. establish a comprehensive catalog of lncRNAs implicated in metabolic regulation and develop a roadmap to identify and characterize functional lncRNAs regulating energy metabolism in vivo. Using this approach, they validate Gm16551 as a lncRNA negative regulator of SREBP1c activity and lipogenesis in the mouse liver.