The broad interest of the Cao group is to understand the complex regulation of energy metabolism and uncover its significance in metabolic physiology and the pathogenesis of metabolic disease. The worldwide obesity epidemic—along with an array of obesity-related disorders, particularly diabetes, fatty liver and cardiovascular diseases—has become a major public health threat in the 21st century. The molecular and pathological basis by which obesity induces metabolic disorders, however, remains only partly understood, hampering the development of effective therapies against these debilitating diseases.
Our current knowledge of energy metabolism is mostly based on studies of protein coding genes, which constitute less than 2% of the human genome. Although the remainder of the genome was initially considered to consist predominantly of gene deserts, thorough examinations of the human transcriptome in recent years have revealed that over 85% of the human genome is transcribed, and human cells express tens of thousands of long noncoding RNAs (lncRNAs). In humans, lncRNAs are at least three times more prevalent than protein-coding genes, and many lncRNAs overlap disease-associated genetic variants, suggesting that they might have important physiological functions. The Cao group has recently demonstrated that a large number of long noncoding RNAs could function as vital metabolic regulators in mice (Cell Metabolism, March 2015, Cell Reports, March 2016 and Cell Metabolism, October 2016). Our findings also suggest that energy metabolism-associated lncRNAs may have systemic regulatory effects, and that the dysregulation of these lncRNAs could be the underlying cause for many metabolic abnormalities.
If human lncRNAs play similar roles as their rodent counterparts, a significant number could function as important regulators of metabolic homeostasis. Understanding their physiological significance could rapidly enhance our understanding of human metabolism and substantially increase the number of potential therapeutic targets for metabolic diseases. However, lncRNA conservation among species is very low, and most human lncRNAs are human-specific, so insights into lncRNA functions derived from rodent-based studies are often not applicable to human physiology. Nevertheless, organismal complexity is much better correlated with the diversity and size of lncRNA transcriptomes than with those of protein-coding genes, suggesting that human-specific lncRNAs might carry out regulatory functions that are unique to humans. To address these intriguing and challenging questions, the Cao group has recently produced humanized mice in which over 90% of the mouse liver cells are replaced by human hepatocytes, or essentially mice carrying a human liver. Using this powerful model, the lab has identified multiple human-specific lncRNAs that regulate critical signaling networks that are unique to human metabolism. The significance of these lncRNAs in human disease is currently being corroborated by studying their functions in samples from patients who suffer from a range of metabolic disorders.