The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells.

Polycomb group proteins initiate and maintain gene silencing through chromatin modifications and contribute to the maintenance of self-renewal in a variety of stem cells. Among polycomb repressive complexes (PRCs), PRC2 initiates gene silencing by methylating histone H3 lysine 27, and PRC1 maintains gene silencing through mono-ubiquitination of histone H2A lysine 119. We have previously shown that Bmi1, a core component of PRC1, tightly regulates the self-renewal of hepatic stem/progenitor cells. In this study, we conducted lentivirus-mediated knockdown of Ezh2 to characterise the function of Ezh2, a major component of PRC2, in hepatic stem/progenitor cells. Loss of Ezh2 function in embryonic murine hepatic stem/progenitor cells severely impaired proliferation and self-renewal capability. This effect was more prominent than that of Bmi1-knockdown and was partially abrogated by the deletion of both Ink4a and Arf, major targets of PRC1 and PRC2. Importantly, Ezh2-knockdown but not Bmi1-knockdown promoted the differentiation and terminal maturation of hepatocytes, followed by the up-regulation of several transcriptional regulators of hepatocyte differentiation. Our findings indicate that Ezh2 plays an essential role in the maintenance of both the proliferative and self-renewal capacity of hepatic stem/progenitor cells and the full execution of their differentiation.

Aoki R ，Chiba T ，Miyagi S ，Negishi M ，Konuma T ，Taniguchi H ，Ogawa M ，Yokosuka O ，Iwama A ... -  《-》

Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells.

Mochizuki-Kashio M ，Mishima Y ，Miyagi S ，Negishi M ，Saraya A ，Konuma T ，Shinga J ，Koseki H ，Iwama A ... -  《-》

Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in mice.

Chiba T ，Seki A ，Aoki R ，Ichikawa H ，Negishi M ，Miyagi S ，Oguro H ，Saraya A ，Kamiya A ，Nakauchi H ，Yokosuka O ，Iwama A ... -  《-》

Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.

Agherbi H ，Gaussmann-Wenger A ，Verthuy C ，Chasson L ，Serrano M ，Djabali M ... -  《PLoS One》

pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.

Kotake Y ，Cao R ，Viatour P ，Sage J ，Zhang Y ，Xiong Y ... -  《-》