Single-cell transcriptomic and genomic changes in the aging human brain.
Single-cell transcriptomic and genomic changes in the aging human brain.
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衰老人脑中的单细胞转录组和基因组变化。
DOI：
10.1101/2023.11.07.566050
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lodato,MichaelA
中科院分区：
文献类型：
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作者：
Jeffries,AilsaM;Yu,Tianxiong;Ziegenfuss,JenniferS;Tolles,AllieK;Kim,Yerin;Weng,Zhiping;Lodato,MichaelA
衰老带来器官和组织中各种过程的失调，通常源于随着时间的推移对单个细胞的随机损伤。在这里，我们使用了单核RNA测序和单细胞全基因组测序的组合来识别人类大脑前额叶皮层在整个生命周期中的转录组和基因组变化，从婴儿到百岁老人。我们确定了婴儿特异性细胞簇，这些细胞簇富含神经发育基因的表达，以及细胞必需的稳态基因的共同下调，这些基因在细胞类型的衰老过程中在核糖体、运输和代谢中发挥作用。相反，神经元特异性基因的表达通常在整个生命过程中保持稳定。我们观察到衰老过程中特定DNA修复基因的减少，包括与产生脑体细胞突变有关的基因，如突变特征分析所示。此外，我们检测到基因长度特异性体细胞突变率，这些突变率塑造了老年人大脑的转录组景观。这些发现阐明了人类大脑衰老的关键方面，揭示了转录组学和基因组学动态。
Aging brings dysregulation of various processes across organs and tissues, often stemming from stochastic damage to individual cells over time. Here, we used a combination of single-nucleus RNA-sequencing and single-cell whole-genome sequencing to identify transcriptomic and genomic changes in the prefrontal cortex of the human brain across life span, from infancy to centenarian. We identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, and a common down-regulation of cell-essential homeostatic genes that function in ribosomes, transport, and metabolism during aging across cell types. Conversely, expression of neuron-specific genes generally remains stable throughout life. We observed a decrease in specific DNA repair genes in aging, including genes implicated in generating brain somatic mutations as indicated by mutation signature analysis. Furthermore, we detected gene-length-specific somatic mutation rates that shape the transcriptomic landscape of the aged human brain. These findings elucidate critical aspects of human brain aging, shedding light on transcriptomic and genomics dynamics.