Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 575, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd2655
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Funding
- National Key Research and Development Program of China [2018YFC2000100, 2017YFA0103304, 2017YFA0102802, 2018YFA0107203, 2015CB964800, 2018YFC2000400, 2017YFA0102702, 2020YFA0804000, 2020YFA0112201, 2020YFA0113400]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16010100]
- National Natural Science Foundation of China [81625009, 81921006, 91749202, 81861168034, 81671377, 81822018, 91749123, 31671429, 91949209, 81701388, 82071588, 81870228, 81922027, 81801399, 31801010, 31900523, 32000510]
- Program of Beijing Municipal Science and Technology Commission [Z191100001519005]
- Beijing Natural Science Foundation [Z190019]
- K. C. Wong Education Foundation [GJTD-2019-06, GJTD-2019-08]
- Key Research Program of the Chinese Academy of Sciences [KFZD-SW-221]
- Advanced Innovation Center for Human Brain Protection [3500-1192012]
- Beijing Municipal Commission of Health and Family Planning [PXM2018_026283_000002]
- Youth Innovation Promotion Association of CAS [2016093]
- Young Elite Scientists Sponsorship Program by CAST [2017QNRC001]
- International Partnership Program of Chinese Academy of Sciences [152111KYSB20160004]
- State Key Laboratory of Membrane Biology
- State Key Laboratory of Stem Cell and Reproductive Biology
- Beijing Advanced Innovation Center for Genomics (ICG) at Peking University
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Understanding the genetic and epigenetic factors of cellular senescence is crucial for developing interventions to slow aging. CRISPR-Cas9-based screens identified genes like KAT7 that alleviate senescence in accelerated aging models, and lentiviral vectors encoding Cas9/sg-Kat7 were effective in alleviating cellular aging and extending lifespan.
Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15(INK4b) transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24(-/-) mice that exhibit a premature aging phenotype. CRISPR-Cas9-based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.
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