Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline.
Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline.
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DOI：
10.1111/acel.12745
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发表时间：
2018-06
期刊：
影响因子：
7.8
通讯作者：
Rugg-Gunn PJ
中科院分区：
文献类型：
--
作者：
Lupo G;Nisi PS;Esteve P;Paul YL;Novo CL;Sidders B;Khan MA;Biagioni S;Liu HK;Bovolenta P;Cacci E;Rugg-Gunn PJ
由于神经干/祖细胞（NSPC）的耗竭和功能损伤，成人神经发生随着年龄的增长而下降。对导致与年龄相关的神经源性缺陷的潜在机制的更好的理解可能会导致减轻认知障碍和促进神经再生的策略的发展。实现这一目标的一个重要步骤是在全基因组范围内研究 NSPC 衰老过程中发生的分子变化。在这项研究中，我们比较了来自年轻成年（3 个月大）和老年（18 个月大）小鼠脑室下区 (SVZ) 的 NSPC 的转录、组蛋白甲基化和 DNA 甲基化特征。令人惊讶的是，SVZ 衍生的 NSPC 的转录和表观基因组谱在衰老细胞中基本没有变化。尽管存在全球相似性，但我们在数百个基因和调控元件上检测到了强烈的年龄依赖性变化，从而确定了神经源性衰退的假定调节因子。在此列表中，在老化 NSPC 中，同源框基因 Dbx2 在体外和体内均上调，并且其启动子区域改变了组蛋白和 DNA 甲基化水平。通过功能性体外测定，我们发现年轻成年 NSPC 中 Dbx2 表达的升高会促进与年龄相关的表型，包括 NSPC 培养物增殖的减少以及 NSPC 增殖和分化的年龄相关调节因子的转录水平的改变。耗尽老化 NSPC 中的 Dbx2 会导致相反的基因表达变化。总而言之，这些结果为小鼠 NSPC 衰老过程中受影响的分子程序提供了新的见解，并揭示了 Dbx2 在促进与年龄相关的神经源性衰退中的新功能作用。
Adult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age‐associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ‐derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age‐dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age‐related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age‐associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age‐related neurogenic decline.
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降低的NRF2表达介导了关键的中年期间神经干细胞功能的下降。
影响因子：
7.8
作者：
Corenblum MJ;Ray S;Remley QW;Long M;Harder B;Zhang DD;Barnes CA;Madhavan L
通讯作者：
Madhavan L
影响因子：
4.6
作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
Morrison, Sean J.
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
5.3
作者：
Maslov, AY;Barone, TA;Pruitt, SC
通讯作者：
Pruitt, SC