通过全基因组CRISPR干扰筛选鉴定复制性衰老和炎性衰老特征
Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.
作者信息
Wu Lingling, Zhu Xiang, Liu Yanxia, Zhao Dehua, Yu Betty Chentzu, Wei Zheng, Lin Xueqiu, Qi Lei S
机构信息
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, 19024, USA.
出版信息
Genome Biol. 2025 Aug 6;26(1):233. doi: 10.1186/s13059-025-03683-7.
BACKGROUND
Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
RESULTS
We perform multiple genome-wide CRISPR interference (CRISPRi) screenings in human primary mesenchymal stem cells derived from adipose tissue during either replicative senescence or inflammation-induced senescence. These screens reveal distinct sets of potential novel regulators specific to each senescence pathway. Combining our perturbation-based functional genomic data with 405 genome-wide association study datasets, including 50 aging-related studies, we find that the inflammatory aging signatures identified from CRISPRi screenings are significantly associated with diverse aging processes, suggesting novel molecular signatures for analyzing and predicting aging status and aging-related disease.
CONCLUSIONS
The signatures verified through comprehensive functional genomics and genetic analyses may provide new targets for modulating the aging process and enhancing the quality of cell therapy products.
背景
衰老 是慢性疾病和癌症的主要风险因素。细胞衰老，尤其是在成体干细胞中，为剖析衰老的分子机制提供了一个高通量框架。
结果
我们在来自脂肪组织的人类原代间充质干细胞的复制性衰老或炎症诱导衰老过程中进行了多次全基因组CRISPR干扰（CRISPRi）筛选。这些筛选揭示了特定于每个衰老途径的不同潜在新调节因子集。将我们基于扰动的功能基因组数据与405个全基因组关联研究数据集（包括50项与衰老相关的研究）相结合，我们发现从CRISPRi筛选中鉴定出的炎症衰老特征与多种衰老过程显著相关，这表明了用于分析和预测衰老状态及衰老相关疾病的新分子特征。
结论
通过全面的功能基因组学和遗传分析验证的特征可能为调节衰老过程和提高细胞治疗产品质量提供新靶点。
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