MicroRNA‐122 regulates polyploidization in the murine liver

Abstract

A defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting ~90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy we examined livers from Dicer1 liver-specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3-fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Secondly, we surveyed age-dependent expression of miRNAs in wild-type mice and identified a subset of miRNAs, including miR-122, that is differentially expressed at 2–3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, life-long depletion of polyploid hepatocytes, proving that miR-122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus-mediated over-expression of miR-122, underscoring the critical role miR-122 plays in polyploidization. Finally, we identified direct targets of miR-122 (Cux1, Rhoa, Iqgap1, Mapre1, Nedd4l and Slc25a34) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation. Conclusion Our data demonstrate that miR-122 is both necessary and sufficient in liver polyploidization. Among the different signals that have been associated with hepatic polyploidy, miR-122 is the first liver-specific signal identified. These studies will serve as the foundation for future work investigating miR-122 in liver maturation, homeostasis and disease.

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

“…Cytokinesis failure and mitotic slippage events have a pivotal role in establishing hepatocyte polyploidy (Celton-Morizur et al, 2009; Hsu et al, 2016; Pandit et al, 2012). Skp2 is a major cytokinetic regulator and a F-box protein that targets p27 for ubiquitination and subsequent degradation to promote cell cycle progression (Carrano et al, 1999; Nakayama et al, 2000; Nakayama et al, 2004).…”

Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer

“…As a predominant miRNA in the liver, miR-122 has been extensively studied and shown to be involved in the regulation of numerous transcripts encoding a variety of hepatic processes, among them, cholesterol and lipid metabolism (Esau et al, 2006; Krützfeldt et al, 2005), mitochondrial function (Burchard et al, 2010), circadian rhythm control (Gatfield et al, 2009; Kojima et al, 2010), polyploidy regulation (Hsu et al, 2016), hepatitis C virus replication (Jopling et al, 2005), and liver tumor suppression (Bai et al, 2009; Gramantieri et al, 2007; Tsai et al, 2009). …”

Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis

“…Most of the miRs are conserved in different species (42, 53, 54). The conservation allows an easy way to evaluate physiological effects of overexpression or loss-of-function of specific miRs in model organisms before human studies.…”