Functional and mechanistic studies of human-specific long noncoding RNAs using a humanized mouse model

National Heart, Lung, And Blood Institute

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Abstract

We have demonstrated that lncRNAs robustly regulate systemic lipid and glucose metabolism and their dysregulation could contribute to the pathogenesis of metabolic disease in mice (Cell Metabolism, 2015, Cell Reports, 2016 and Cell Metabolism, 2016). If lncRNAs play a similar role in human, understanding their functions could provide important insights into human metabolic physiology and open up novel therapeutic strategies. However, lncRNAs are much less conserved among species and it is estimated that majority (81%) of human lncRNAs are either primate- or human-specific (Nature 2014 Jan 30; 505) and their physiological function cannot be adequately studied in animal models. To develop a system to study the physiological role of human lncRNAs in energy metabolism, we have successfully produced liver-specific humanized mice in which over 90% mouse hepatocytes are replaced by engrafted human hepatocytes. We have recently identified a number of human-specific and liver-enriched lncRNAs that exhibit altered expression in patient samples or are genetically associated with metabolic diseases. Knockdown of selected lncRNAs in the humanize mice indicates human lncRNAs play an important role in metabolic physiology and could be potential therapeutic targets for metabolic disorders (Nature Communications, 2020 and Journal of Clinical Investigation, 2021).