A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence
A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence
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基于 CRISPR 的全基因组筛选确定 KAT7 是细胞衰老的驱动因素
DOI：
10.1126/scitranslmed.abd2655
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发表时间：
2021-01-06
影响因子：
17.1
通讯作者：
Liu, Guang-Hui
中科院分区：
文献类型：
--
作者：
Wang, Wei;Zheng, Yuxuan;Liu, Guang-Hui
了解细胞衰老的遗传和表观遗传基础对发展缓慢衰老的干预措施具有重要作用。我们使用表现出加速衰老的两种类型的人间充质前体细胞（HMPC）进行了基于基因组CRISPR-CAS9的筛选。 HMPC源自携带致病性突变的人类胚胎干细胞，这些突变引起加速衰老疾病Werner综合征和Hutchinson-Gilford Progeria综合征。鉴定出缺乏缺乏减轻细胞衰老的基因，包括KAT7，一种组蛋白乙酰转移酶，在两个后代HMPC模型中都排名最高。 Kat7的失活减少了组蛋白H3赖氨酸14乙酰化，抑制P15（INK4B）转录，并减轻了HMPC衰老。此外，静脉注射的慢病毒载体编码CAS9/SG-KAT7，减轻了肝细胞衰老和肝老化的肝细胞衰老，并在生理上老化的小鼠以及前代ZMPSTE24（ - - - ）小鼠的肝脏衰老和延长的寿命跨度。基于CRISPR-CAS9的基因筛选是系统地揭示诸如KAT7之类的衰老基因的强大方法，这可能代表了发展衰老干预措施的治疗靶标。
Inactivation of the histone acetyltransferase gene KAT7 prolongs survival in naturally aged mice and progeroid mice that age prematurely. Slowing cellular senescence Whereas cellular senescence is known to promote aging, many of the mechanisms controlling this process remain poorly understood. Using human mesenchymal precursor cells (hMPCs) carrying pathogenic mutations of the premature aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome, the authors conducted a genome-wide CRISPR-Cas9–based screen to identify genes that could affect cellular senescence. They identified KAT7, a histone acetyltransferase gene, as a driver of senescence. Inactivation of Kat7 in mice aging normally and in prematurely aging progeroid mice extended their life span. Although KAT7 requires further study in other cell types, these experiments highlight the utility of genome-wide CRISPR-Cas9 screens and shed further light on mechanisms controlling senescence. Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.