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- W4220700100 abstract "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. Apolipoprotein E (APOE) is a lipoprotein particle component and is genetically linked to human longevity and Alzheimer’s disease; however, the mechanisms that link APOE and aging are incompletely understood. Here, Zhao et al. show that APOE drives cellular senescence in aged human mesenchymal progenitor cells by destabilizing heterochromatin." @default.
- W4220700100 created "2022-04-03" @default.
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- W4220700100 date "2022-03-28" @default.
- W4220700100 modified "2023-10-18" @default.
- W4220700100 title "Destabilizing heterochromatin by APOE mediates senescence" @default.
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