JMJD3 mediated senescence is required to overcome stress induced hematopoietic defects

Author:

Nakata Yuichiro,Ueda TakeshiORCID,Sera Yasuyuki,Kanai Akinori,Ikeda Ken-ichiro,Yamasaki Norimasa,Nagamachi Akiko,Kobatake Kohei,Taguchi Masataka,Sotomaru Yusuke,Ichinohe Tatsuo,Honda Zen-ichiro,Manabe Ichiro,Suda Toshio,Takubo KeiyoORCID,Kaminuma Osamu,Honda Hiroaki

Abstract

AbstractCellular 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 viap16Ink4aupregulation in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. JMJD3 deficiency impaired stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress conditions. These impaired phenotypes were rescued through exogenous and retroviral introduction ofp16Ink4a. This JMJD3-p16INK4aaxis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a JMJD3 selective inhibitor attenuated leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4amediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress conditions, suggesting a new link for aging and anti-cancer therapies.

Publisher

Cold Spring Harbor Laboratory

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