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.
基金：
National Key Research and Development Program of China [2021YFF1201000, 2020YFA0112200, 2020YFA0113400, 2020YFA0804000, 2020YFA0803401, 2019YFA0802202, 2019YFA0110100, 2018YFA0107203, 2018YFC2000400, 2017YFA0103304, 2017YFA0102802, 2018YFC2000100]; Strategic Priority Research Program of CAS [XDA16010000]; Beijing Natural Science Foundation [Z190019, JQ20031]; National Natural Science Foundation of China [81901433, 81921006, 81625009, 91749202, 81861168034, 91949209, 82125011, 92049304, 92049116, 81822018, 81870228, 81922027, 82071588, 82122024, 32100937, 32121001, 31970597, 81801399]; Program of the Beijing Municipal Science and Technology Commission [Z191100001519005]; Key Research Program of the Chinese Academy of Sciences [KFZD-SW-221]; K. C. Wong Education Foundation [GJTD-2019-06, GJTD-2019-08]; 14th Five-year Network Security and Informatization Plan of CAS [WX145XQ07-18]; Science and Technology Service Network Initiative of CAS [KFJ-STS-QYZD-2021-08-001]; CAS Special Research Assistant Program, Youth Innovation Promotion Association of CAS [E1CAZW0401, 2020085]; CAS Project for Young Scientists in Basic Research [YSBR-012]; Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences [2020-JKCS-011]; State Key Laboratory of Stem Cell and Reproductive Biology; Milky Way Research Foundation; State Key Laboratory of Membrane Biology
医学