Ring1B promotes hepatic stem/progenitor cell expansion through simultaneous suppression of Cdkn1a and Cdkn2a in mice

Authors

  • Hiroyuki Koike,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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    • These authors contributed equally to this work.

  • Yasuharu Ueno,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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    • These authors contributed equally to this work.

  • Takako Naito,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Tomoya Shiina,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Susumu Nakata,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan
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  • Rie Ouchi,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Yuta Obana,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Keisuke Sekine,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Yun-Wen Zheng,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Takanori Takebe,

    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
    2. Project Leader of Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
    3. PRESTO, Japan Science and Technology Agency, Tokyo, Japan
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  • Kyo-ichi Isono,

    1. Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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  • Haruhiko Koseki,

    1. Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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  • Hideki Taniguchi

    Corresponding author
    1. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
    2. Project Leader of Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
    • Address reprint requests to: Hideki Taniguchi, M.D., Ph.D., The Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. E-mail: rtanigu@med.yokohama-cu.ac.jp; fax: +81-45-787-8963.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the Special Coordination Funds for Promoting Science (11800122), grants from Stategic Promotion of Innovative Research and Development (S-innovation, 62890004), the Grant-in-Aid for Scientific Research on Innovative Area,s and the Japan Health Sciences Foundation of the Japan Science and Technology Agency (JST). This work was also supported by the Grants-in Aid (nos. 20591532, 21249071, 22390260, 23791490, 23791491, 24106510, and 24689052) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, by the Specified Research Grant from Takeda Science Foundation, by a grant from Yokohama Foundation for Advanced Medical Science, and by a grant from the Japan Insulin Dependent Diabetes Mellitus (IDDM) network.

Abstract

Polycomb-group (PcG) proteins play crucial roles in self-renewal of stem cells by suppressing a host of genes through histone modifications. Identification of the downstream genes of PcG proteins is essential for elucidation of the molecular mechanisms of stem cell self-renewal. However, little is known about the PcG target genes in tissue stem cells. We found that the PcG protein, Ring1B, which regulates expression of various genes through monoubiquitination of histone H2AK119, is essential for expansion of hepatic stem/progenitor cells. In mouse embryos with a conditional knockout of Ring1B, we found that the lack of Ring1B inhibited proliferation and differentiation of hepatic stem/progenitor cells and thereby inhibited hepatic organogenesis. These events were characterized by derepression of cyclin-dependent kinase inhibitors (CDKIs) Cdkn1a and Cdkn2a, known negative regulators of cell proliferation. We conducted clonal culture experiments with hepatic stem/progenitor cells to investigate the individual genetic functions of Ring1B, Cdkn1a, and Cdkn2a. The data showed that the cell-cycle inhibition caused by Ring1B depletion was reversed when Cdkn1a and Cdkn2a were suppressed simultaneously, but not when they were suppressed individually. Conclusion: Our results show that expansion of hepatic stem/progenitor cells requires Ring1B-mediated epigenetic silencing of Cdkn1a and Cdkn2a, demonstrating that Ring1B simultaneously regulates multiple CDKIs in tissue stem/progenitor cells. (Hepatology 2014;60:323-333)

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