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Ring1B promotes hepatic stem/progenitor cell expansion through simultaneous suppression of Cdkn1a and Cdkn2a in mice
Author(s) -
Koike Hiroyuki,
Ueno Yasuharu,
Naito Takako,
Shiina Tomoya,
Nakata Susumu,
Ouchi Rie,
Obana Yuta,
Sekine Keisuke,
Zheng YunWen,
Takebe Takanori,
Isono Kyoichi,
Koseki Haruhiko,
Taniguchi Hideki
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27046
Subject(s) - progenitor cell , stem cell , biology , cdkn2a , microbiology and biotechnology , epigenetics , cancer research , genetics , gene
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. (H epatology 2014;60:323‐333)