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

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-06-25 DOI:10.1038/s44319-025-00502-9

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

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引用次数: 0

Abstract

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^Ink4a 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^Ink4a. This JMJD3-p16^INK4a 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^INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress.

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jmjd3介导的衰老是克服应激诱导的造血缺陷所必需的。

干细胞的细胞衰老损害再生能力，促进慢性炎症，并与衰老有关。造血干细胞和祖细胞（HSPCs）负责产生成熟的血细胞，然而，细胞衰老如何影响其功能在很大程度上是未知的。在这里，我们发现JMJD3，一种组蛋白去甲基化酶，通过上调p16Ink4a与Polycomb组蛋白竞争来激活细胞衰老，并重新编程HSPC完整性以克服由复制和致癌应激诱导的造血缺陷。Jmjd3缺乏不会改变H3K27me3的整体水平，这表明Jmjd3在逆境下通过表观遗传调控特定的和有限的Jmjd3靶点。JMJD3缺乏也会损害应激下HSPCs的干细胞潜能、适当的细胞周期调节和WNT通路激活。这些受损的表型是通过外源性和逆转录病毒导入p16Ink4a来恢复的。造血中的JMJD3-p16INK4a轴是年龄依赖性的，与细胞衰老不同。用选择性JMJD3抑制剂治疗可减弱细胞衰老期间的白血病潜能。综上所述，这些结果表明JMJD3-p16INK4a介导细胞衰老，并在应激下HSPCs的功能完整性中发挥关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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