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

Authors

• L Yang
• P Li
• W Yang
• X R
• K Kiesewetter
• J Zhu
• H Cao

Abstract

The long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides without protein coding potential. The number of lncRNA genes exceeds the number of protein-coding genes in mouse and human genomes. However, the physiological function of lncRNAs is largely unknown. To evaluate the significance of lncRNAs, and identify the functional lncRNAs in systemic metabolism in mice, we performed over 100 transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Similar to mRNAs, lncRNA transcriptome in each tissue forms a metabolic signature reflecting the animal’s metabolic or disease condition. Out of 7,608 regulated lncRNAs, function-orientated filters yield 541 tissue-specifically regulated and metabolically sensitive lncRNAs, which are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by individual nutrients, metabolic hormones and key transcription factors were further defined in primary hepatocytes connecting these lncRNAs to metabolic signaling pathways. Combining the extensive genomewide screens, bioinformatics function predictions and cell-based analyses, we have developed an integrative roadmap to identify functional lncRNA metabolic regulators in vivo. Mice with liver-specific knockdown of an SREBP1c-inducible lncLMS, predicted to regulate lipid metabolism by our roadmap, exhibit elevated lipogenic gene expressions and circulating levels of triglyceride. Taken together, this study identifies a class of lncRNAs function as important metabolic regulators, and establishes a framework for investigating the role of lncRNAs in physiological homeostasis.

Scientific Focus Area: Molecular Biology and Biochemistry

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