UHRF1 is required for basal stem cell proliferation in response to airway injury.
UHRF1 is required for basal stem cell proliferation in response to airway injury.
复制标题
UHRF1是气道损伤时基底干细胞增殖所必需的。
DOI：
10.1038/celldisc.2017.19
复制
发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Wang XF
中科院分区：
文献类型：
--
作者：
Xiang H;Yuan L;Gao X;Alexander PB;Lopez O;Lau C;Ding Y;Chong M;Sun T;Chen R;Liu SQ;Wu H;Wan Y;Randell SH;Li QJ;Wang XF
细胞衰老是一种以不可逆的细胞周期停滞为特征的细胞命运，但这种衰老标志的分子机制仍然知之甚少。通过对气道基底细胞中新型衰老调节因子的无偏搜索，我们发现具有PHD和含环指结构域蛋白1（UHRF1）的表观遗传调节因子泛素样对调节细胞周期进程至关重要。损伤后，小鼠气道中的基底细胞迅速诱导UHRF 1的表达，以刺激干细胞增殖和组织修复。特异性地在气道基底细胞中靶向去除Uhrf1导致细胞周期进展的严重缺陷。一致地，培养的缺乏UHRF 1的原代人基底细胞不表现出细胞死亡或分化表型，但经历自发的衰老程序。从机制上讲，UHRF 1的丢失通过废除DNA复制工厂的形成诱导G1细胞周期停滞，如增殖细胞核抗原（PCNA）斑点的丢失和无法进入第一个细胞周期所证明的。这种增殖缺陷部分由p15途径介导。总的来说，我们的研究提供了第一个证据，在气道再生过程中，UHRF1在体干细胞增殖中起着不可或缺的作用。
Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.