Nakata Yuichiro, Ueda Takeshi, Sera Yasuyuki, Koizumi Miho, Imamura Katsutoshi, Kanai Akinori, Ikeda Ken-Ichiro, Yamasaki Norimasa, Nagamachi Akiko, Kobatake Kohei, Taguchi Masataka, Sotomaru Yusuke, Ichinohe Tatsuo, Honda Zen-Ichiro, Nakamura Takuro, Manabe Ichiro, Suda Toshio, Takubo Keiyo, Kaminuma Osamu, Honda Hiroaki
Department of Systems Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Biochemistry, Faculty of Medicine, Kindai University, Osakasayama, Japan.
EMBO Rep. 2025 Jun 25. doi: 10.1038/s44319-025-00502-9.
Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence by upregulating p16 in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. Jmjd3 deficiency does not alter global H3K27me3 levels, indicating that JMJD3 epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3 deficiency also impairs stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress. These impaired phenotypes are rescued through exogenous and retroviral introduction of p16. This JMJD3-p16 axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a selective JMJD3 inhibitor attenuates leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16 mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress.
干细胞中的细胞衰老会损害再生能力，促进慢性炎症，并与衰老相关。造血干细胞和祖细胞（HSPCs）负责产生成熟血细胞，然而，细胞衰老如何影响其功能在很大程度上尚不清楚。在此，我们表明，组蛋白去甲基化酶JMJD3通过与多梳蛋白家族蛋白竞争上调p16来激活细胞衰老，并重新编程HSPC的完整性以克服由复制性和致癌性应激诱导的造血缺陷。Jmjd3缺陷不会改变整体H3K27me3水平，表明JMJD3在应激条件下对特定且有限的JMJD3靶点进行表观遗传调控。Jmjd3缺陷还会损害应激条件下HSPCs的干细胞潜能、适当的细胞周期调控和WNT通路激活。通过外源性和逆转录病毒导入p16可挽救这些受损表型。造血过程中的这条JMJD3-p16轴具有年龄依赖性，且与细胞衰老不同。用选择性JMJD3抑制剂治疗可在细胞衰老期间减弱白血病潜能。综上所述，这些结果表明JMJD3-p16介导细胞衰老，并在应激条件下HSPCs的功能完整性中发挥关键作用。
