Identification of KAT7 as the Driver of Cellular Senescence by Genome-Wide Screening with CRISPR/Cas9

A genome-wide CRISPR screen identifies KAT7 to be a driver of cell senescence

While cellular senescence has been shown to accelerate aging, the mechanisms that control this process are still poorly understood. The authors used human mesenchymal progenitor cells (hMPCs), which carried pathogenic mutations for the early aging diseases Werner Syndrome and Hutchinson Gilford Progeria Syndrome, to conduct a genome-wide CRISPR/Cas9 screen in order to identify genes involved in cellular senescence. The authors identified KAT7 (a histone-acetyltransferase) as the driver of senescence. Inactivation Kat7 in mice that age normally or prematurely in progeroid mice increased their lifespan. These experiments, although KAT7 needs to be studied in other cell types and shed more light on mechanisms controlling the senescence process, highlight the utility genome-wide CRISPR/Cas9 screens.

Understanding the genetics and epigenetics of cellular aging is crucial to developing interventions that slow down aging. Two types of human mesenchymal progenitor cells (hMPCs), which exhibit accelerated senescence, were used to perform genome-wide CRISPR/Cas9 screens. The hMPCs are derived from human stem cells that carry pathogenic mutations causing the accelerated ageing diseases Hutchinson Gilford progeria and Werner syndrome. KAT7 was identified as the top gene that alleviated cell senescence. This histone acetyltransferase is also a major hit in progeroid hMPCs. Inactivation KAT7 decreased H3 lysine 14, repressed transcription of p15INK4b, and reduced hMPCs senescence.

Source:
https://stm.sciencemag.org/content/13/575/eabd2655

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