Destabilizing heterochromatin by APOE mediates senescence.

Humans Aged Heterochromatin / genetics Apolipoproteins E / genetics Cellular Senescence / genetics Aging / genetics Chromobox Protein Homolog 5 Nuclear Proteins / genetics

Journal

Nature aging
ISSN: 2662-8465
Titre abrégé: Nat Aging
Pays: United States
ID NLM: 101773306

Informations de publication

Date de publication:
04 2022
Historique:
received: 01 04 2021
accepted: 01 02 2022
medline: 1 5 2023
pubmed: 29 4 2023
entrez: 28 4 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s43587-022-00186-z PMID: 37117743
pubmed: 37117743
doi: 10.1038/s43587-022-00186-z
pii: 10.1038/s43587-022-00186-z
doi:

Substances chimiques

Heterochromatin 0
Apolipoproteins E 0
Chromobox Protein Homolog 5 107283-02-3
Nuclear Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

303-316

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Hongkai Zhao (H)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Science and Technology of China, Hefei, China.

Qianzhao Ji (Q)

University of the Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Zeming Wu (Z)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Si Wang (S)

Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
Chongqing Renji Hospital, University of the Chinese Academy of Sciences, Chongqing, China.

Jie Ren (J)

University of the Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Chinese Academy of Sciences Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
China National Center for Bioinformation, Beijing, China.
ORCID: 0000-0002-6450-3163

Kaowen Yan (K)

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Zehua Wang (Z)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of the Chinese Academy of Sciences, Beijing, China.

Jianli Hu (J)

University of the Chinese Academy of Sciences, Beijing, China.
Chinese Academy of Sciences Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
China National Center for Bioinformation, Beijing, China.

Qun Chu (Q)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Huifang Hu (H)

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Yusheng Cai (Y)

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Qiaoran Wang (Q)

University of the Chinese Academy of Sciences, Beijing, China.
Chinese Academy of Sciences Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
China National Center for Bioinformation, Beijing, China.

Daoyuan Huang (D)

Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.

Zhejun Ji (Z)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Jingyi Li (J)

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.

Juan Carlos Izpisua Belmonte (JCI)

Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
ORCID: 0000-0003-0557-8875

Moshi Song (M)

University of the Chinese Academy of Sciences, Beijing, China. songmoshi@ioz.ac.cn.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. songmoshi@ioz.ac.cn.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. songmoshi@ioz.ac.cn.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. songmoshi@ioz.ac.cn.

Weiqi Zhang (W)

University of the Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
Chinese Academy of Sciences Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
China National Center for Bioinformation, Beijing, China. zhangwq@big.ac.cn.
ORCID: 0000-0002-8885-5104

Jing Qu (J)

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
University of Science and Technology of China, Hefei, China. qujing@ioz.ac.cn.
University of the Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. qujing@ioz.ac.cn.
ORCID: 0000-0002-3988-5067

Guang-Hui Liu (GH)

University of the Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. ghliu@ioz.ac.cn.
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.
Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.
ORCID: 0000-0001-9289-8177

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Hétérochromatine › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Vieillissement › Vieillissement de la cellule › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Vieillissement › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Homologue-5 de la protéine chromobox › Destabilizing heterochromatin by APOE mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Destabilizing heterochromatin by APOE mediates...