Abstract
Mouse is the most widely used animal model in biomedical research, but it remains unknown what causes the large number of differentially regulated genes between human and mouse livers identified in recent years. In this report, we aim to determine whether these divergent gene regulations are primarily caused by environmental factors or some of them are the result of cell-autonomous differences in gene regulation in human and mouse liver cells. The latter scenario would suggest that many human genes are subject to human-specific regulation and can only be adequately studied in a human or humanized system. To understand the similarity and divergence of gene regulation between human and mouse livers, we performed stepwise comparative analyses in human, mouse, and humanized livers with increased stringency to gradually remove the impact of factors external to liver cells, and used bioinformatics approaches to retrieve gene networks to ascertain the regulated biological processes. We first compared liver gene regulation by fatty liver disease in human and mouse under the condition where the impact of genetic and gender biases was minimized, and identified over 50% of all commonly regulated genes, that exhibit opposite regulation by fatty liver disease in human and mouse. We subsequently performed more stringent comparisons when a single specific transcriptional or post-transcriptional event was modulated in vitro or vivo or in liver-specific humanized mice in which human and mouse hepatocytes colocalize and share a common circulation. Intriguingly and strikingly, the pattern of a high percentage of oppositely regulated genes persists under well-matched conditions, even in the liver of the humanized mouse model, which represents the most closely matched in vivo condition for human and mouse liver cells that is experimentally achievable. Gene network analyses further corroborated the results of oppositely regulated genes and revealed substantial differences in regulated biological processes in human and mouse cells. We also identified a list of regulated lncRNAs that exhibit very limited conservation and could contribute to these differential gene regulations. Our data support that cell-autonomous differences in gene regulation might contribute substantially to the divergent gene regulation between human and mouse livers and there are a significant number of biological processes that are subject to human-specific regulation and need to be carefully considered in the process of mouse to human translation.
Highlights
The liver occupies a critical role in metabolic homeostasis, and metabolic diseases of the liver, in particular nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), have become major global causes of liver-related morbidity and mortality [1]
Previous comparative analyses have revealed a significant number of differentially regulated genes in human and mouse livers [7,8] but these comparisons were often made between humans of diverse genetic backgrounds and inbred mice of a pure strain
To minimize the impact of the inequivalence of gender and genetic complexity during comparison, we compare the regulation of liver gene expressions by fatty liver disease in human and mouse samples which are composed of diverse genetic makeups and the same gender
Summary
The liver occupies a critical role in metabolic homeostasis, and metabolic diseases of the liver, in particular nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), have become major global causes of liver-related morbidity and mortality [1]. The pathophysiology of the human liver, remains incompletely understood hindering the development of effective therapies for these debilitating diseases. Due to the intrusive nature of liver biopsy, the study of human liver physiology heavily relies on the usage of animal models mouse. Mouse-based studies have led to the development of novel therapeutics for human diseases, their translation rate remains very low [2,3], suggesting there are major differences in physiological responses between the two species. We need to better understand the similarity and divergence of the pathophysiology between human and mouse livers so we can better utilize mice to model human diseases and at the same time identify critical areas where mouse is not a good model for human physiology
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