The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function
The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function
复制标题
DOI：
10.3324/haematol.2018.213009
复制
发表时间：
2020-01-31
期刊：
影响因子：
10.1
通讯作者：
Geiger, Hartmut
中科院分区：
文献类型：
--
作者：
Brown, Andreas;Schuetz, Desiree;Geiger, Hartmut
小鼠造血干细胞和祖细胞的百分比，其在用遗传毒性剂羟基脲治疗后表现出功能丧失，与近交系小鼠的平均寿命呈负相关，包括长寿的C57 B116和短命的DBA/2品系。在BXD重组近交系中的数量性状基因座定位确定了11号染色体近端部分上跨越12.5 cM的区域，该区域与功能失调的造血干细胞和祖细胞的百分比以及寿命的调节有关。通过生成和分析该基因座的相互同源小鼠，我们证明了该区域确实决定了造血干细胞和祖细胞对羟基脲的敏感性。这些细胞不存在如先前预期的细胞周期分布差异;它们也不存在经历细胞凋亡、衰老、复制停滞和重新启动活性的细胞频率的变化，排除了增殖、复制或活力变化是这些细胞与同源株和亲本株的不同反应的基础的可能性。在与DBA/2基因座同源的C57 BL/6小鼠中，血细胞中的表观遗传老化dock加速。我们验证了垂体肿瘤转化基因1（Pttg 1）/Securin作为数量性状基因调节造血干细胞和祖细胞对羟基脲治疗的差异反应，因此可能与寿命的调节有关。
The percentage of murine hematopoietic stem and progenitor cells, which present with a loss of function upon treatment with the genotoxic agent hydroxyurea, is inversely correlated to the mean lifespan of inbred mice, including the long-lived C57B116 and short-lived DBA/2 strains. Quantitative trait locus mapping in BXD recombinant inbred strains identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. By generating and analyzing reciprocal congenic mice for this locus, we demonstrate that this region indeed determines the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. These cells do not present, as previously anticipated, with differences in cell cycle distribution; neither do they present with changes in the frequency of cells undergoing apoptosis, senescence, replication stalling and re-initiation activity, excluding the possibility that variations in proliferation, replication or viability underlie the distinct response of these cells from the congenic and parental strains. An epigenetic aging dock in blood cells was accelerated in C57BL/6 mice congenic for the DBA/2 version of the locus. We verified pituitary tumor-transforming gene1 (Pttg1)/Securin as the quantitative trait gene regulating the differential response of hematopoietic stem and progenitor cells to hydroxyurea treatment and which might therefore be linked to the regulation of lifespan.