MicroRNA‐122 regulates polyploidization in the murine liver
Open accessAbstract
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. Second, 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, lifelong 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 overexpression 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: Among the different signals that have been associated with hepatic polyploidy, miR‐122 is the first liver‐specific signal identified; our data demonstrate that miR‐122 is both necessary and sufficient in liver polyploidization, and these studies will serve as the foundation for future work investigating miR‐122 in liver maturation, homeostasis, and disease. (H epatology 2016;64:599‐615)
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Rhoa, Mapre1, Racgap1, and Slc25a34 are direct targets of miR-122 and, when depleted forcibly, cause a marked increase in binucleate hepatocytes.
“We also measured the mRNA levels of cytokinesis-associated factors Rhoa, Mapre1, Racgap1, and Slc25a34, which are direct targets of miR-122 and, when depleted forcibly, cause a marked increase in binucleate hepatocytes (Hsu et al. 2016).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
The Results section identifies Rhoa, Mapre1, and Slc25a34 as direct miR-122 targets and reports increased binucleate hepatocytes after each was depleted. Racgap1 depletion also increased binucleate hepatocytes, but the paper does not identify Racgap1 as a direct target; it says Racgap1 lacks a miR-122 seed-matching sequence and is regulated via Cux1. Page numbers were not provided in the passages. (LLM, conf=0.94)
Experimental — accuracy not yet measuredBetween P14 and P21, a specialized mitotic program involving programmed cytokinesis failure promotes rapid binucleation and polyploidization of hepatocytes.
“However, between P14 and P21, a specialized mitotic program involving programmed cytokinesis failure promotes rapid binucleation and polyploidization of hepatocytes (Margall-Ducos et al. 2007; Gentric and Desdouets 2014; Hsu et al. 2016).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
The liver-enriched microRNA miR-122 is induced during postnatal development and stimulates physiological polyploidization of hepatocytes by inhibiting the expression of a set of procytokinesis targets.
“Prior studies have demonstrated that the liver-enriched microRNA miR-122 is induced during postnatal development and stimulates physiological polyploidization of hepatocytes by inhibiting the expression of a set of procytokinesis targets (Hsu et al. 2016).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
Hepatic miR-122 expression surged during the first 4 weeks of life.
“In agreement with earlier reports (Xu et al. 2010; Hsu et al. 2016), hepatic miR-122 expression surged during the first 4 weeks of life (Fig. 5B).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
More than 95% of mouse hepatocytes at the P14 stage are diploid, and their binucleation status can be tracked over time in vitro.
“More than 95% of mouse hepatocytes at the P14 stage are diploid, and their binucleation status can be tracked over time in vitro (Hsu et al. 2016).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
A postnatal surge in miR-122 is required for the physiological polyploidization of hepatocytes.
“This was particularly interesting because a postnatal surge in miR-122 is required for the physiological polyploidization of hepatocytes (Hsu et al. 2016; Celton-Morizur and Desdouets 2017).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Hsu et al. 2016
miR-122, one of the most abundant microRNAs in the liver, regulates physiological hepatocyte polyploidisation during postnatal growth.
“Additionally, miR-122, one of the most abundant microRNAs in the liver, regulates physiological hepatocyte polyploidisation during postnatal growth.71”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [71]
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Self-citation
- Authors
- Hsu, S., Delgado, E. R., Otero, P. A., Teng, K., Kutay, H., Meehan, K. M., Moroney, J. B., Monga, J. K., Hand, N. J., Friedman, J. R., Ghoshal, K., & Duncan, A. W.
- Affiliations
- National Taiwan University (TW)
- University of Pittsburgh (US)
- The Ohio State University (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Ghoshal, Kalpana
- Duncan, Andrew W.
- ORCID
- Venue
- Hepatology
- Published
- 2016-05-12
- Volume
- 64
- Issue
- 2
- Pages
- 599-615
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4956491
- OpenAlex
- W2303133052
- Cited by
- 84
- References
- 9
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 10 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 14 · 2017: 12 · 2016: 2
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health
- National Cancer Institute (R01CA193244, P30CA016058)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103645)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- miR-122, polyploidization, hepatocyte polyploidy, cytokinesis failure, liver development, miRNA target genes, CUX1, RhoA, IQGAP1, MAPRE1, NEDD4L, liver homeostasis
- MeSH terms
- Animals, Liver, Mice, Inbred C57BL, Polyploidy, Mice, Knockout, Hepatocytes, MicroRNAs, Cytokinesis
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