Scholarlink

<p>Cellular senescence in stem cells compromises regenerative capacity,promotes chronic inflammation, and is implicated in aging. Hematopoietic stem andprogenitor cells (HSPCs) are responsible for producing mature blood cells, however,how cellular senescence influences their function is largely unknown. Here, we showthat JMJD3, a histone demethylase, activates cellular senescence by upregulating<i>p16</i><sup><i>Ink4a</i></sup> in competition with Polycomb group proteins,and reprograms HSPC integrity to overcome hematopoietic defects induced byreplicative and oncogenic stresses. <i>Jmjd3</i>deficiency does not alter global H3K27me3 levels, indicating that JMJD3epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3deficiency also impairs stem cell potential, proper cell cycle regulation, and WNTpathway activation in HSPCs under stress. These impaired phenotypes are rescuedthrough exogenous and retroviral introduction of <i>p16</i><sup><i>Ink4a</i></sup>. This JMJD3-p16<sup>INK4a</sup>axis in hematopoiesis is age-dependent and is distinct from cellular senescence.Treatment with a selective JMJD3 inhibitor attenuates leukemic potential duringcellular senescence. Taken together, these results demonstrate thatJMJD3-p16<sup>INK4a</sup> mediates cellular senescence and playscritical roles in the functional integrity of HSPCs under stress.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月25日

查看全文
  • Yuichiro Nakata,
  • Takeshi Ueda,
  • Yasuyuki Sera,
  • Miho Koizumi,
  • Katsutoshi Imamura,
  • Akinori Kanai,
  • Ken-ichiro Ikeda,
  • Norimasa Yamasaki,
  • Akiko Nagamachi,
  • Kohei Kobatake,
  • Masataka Taguchi,
  • Yusuke Sotomaru,
  • Tatsuo Ichinohe,
  • Zen-ichiro Honda,
  • Takuro Nakamura,
  • Ichiro Manabe,
  • Toshio Suda,
  • Keiyo Takubo,
  • Osamu Kaminuma,
  • Hiroaki Honda

摘要

Cellular senescence in stem cells compromises regenerative capacity,promotes chronic inflammation, and is implicated in aging. Hematopoietic stem andprogenitor cells (HSPCs) are responsible for producing mature blood cells, however,how cellular senescence influences their function is largely unknown. Here, we showthat JMJD3, a histone demethylase, activates cellular senescence by upregulatingp16Ink4a in competition with Polycomb group proteins,and reprograms HSPC integrity to overcome hematopoietic defects induced byreplicative and oncogenic stresses. Jmjd3deficiency does not alter global H3K27me3 levels, indicating that JMJD3epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3deficiency also impairs stem cell potential, proper cell cycle regulation, and WNTpathway activation in HSPCs under stress. These impaired phenotypes are rescuedthrough exogenous and retroviral introduction of p16Ink4a. This JMJD3-p16INK4aaxis in hematopoiesis is age-dependent and is distinct from cellular senescence.Treatment with a selective JMJD3 inhibitor attenuates leukemic potential duringcellular senescence. Taken together, these results demonstrate thatJMJD3-p16INK4a mediates cellular senescence and playscritical roles in the functional integrity of HSPCs under stress.