论文题目：Destabilizing heterochromatin by APOE mediates senescence

作者：

• Hongkai Zhao, 

• Qianzhao Ji, 

• Zeming Wu, 

• Si Wang, 

• Jie Ren, 

• Kaowen Yan, 

• Zehua Wang, 

• Jianli Hu, 

• Qun Chu, 

• Huifang Hu, 

• Yusheng Cai, 

• Qiaoran Wang, 

• Daoyuan Huang, 

• Zhejun Ji, 

• Jingyi Li, 

• Juan Carlos Izpisua Belmonte, 

• Moshi Song, 

• Weiqi Zhang, 

• Jing Qu & 

• Guang-Hui Liu

日期：2022.3

发表期刊：Nature Aging

doi：10.1038/s43587-022-00186-z

摘要：

    Apolipoprotein E (APOE) is a component of lipoprotein particles that function in the homeostasis of cholesterol and other lipids. Although APOE is genetically associated with human longevity and Alzheimer’s disease, its mechanistic role in aging is largely unknown. Here, we used human genetic, stress-induced and physiological cellular aging models to explore APOE-driven processes in stem cell homeostasis and aging. We report that in aged human mesenchymal progenitor cells (MPCs), APOE accumulation is a driver for cellular senescence. By contrast, CRISPR–Cas9-mediated deletion of APOE endows human MPCs with resistance to cellular senescence. Mechanistically, we discovered that APOE functions as a destabilizer for heterochromatin. Specifically, increased APOE leads to the degradation of nuclear lamina proteins and a heterochromatin-associated protein KRAB-associated protein 1 via the autophagy–lysosomal pathway, thereby disrupting heterochromatin and causing senescence. Altogether, our findings uncover a role of APOE as an epigenetic mediator of senescence and provide potential targets to ameliorate aging-related diseases.