Abstract
The aberrant expression of methyltransferase Set7/9 plays a role in various diseases. However, the contribution of Set7/9 in ischemic stroke remains unclear. Here, we show ischemic injury results in a rapid elevation of Set7/9, which is accompanied by the downregulation of Sirt5, a deacetylase reported to protect against injury. Proteomic analysis identifies the decrease of chromobox homolog 1 (Cbx1) in knockdown Set7/9 neurons. Mechanistically, Set7/9 promotes the binding of Cbx1 to H3K9me2/3 and forms a transcription repressor complex at the Sirt5 promoter, ultimately repressing Sirt5 transcription. Thus, the deacetylation of Sirt5 substrate, glutaminase, which catalyzes the hydrolysis of glutamine to glutamate and ammonia, is decreased, promoting glutaminase expression and triggering excitotoxicity. Blocking Set7/9 eliminates H3K9me2/3 from the Sirt5 promoter and normalizes Sirt5 expression and Set7/9 knockout efficiently ameliorates brain ischemic injury by reducing the accumulation of ammonia and glutamate in a Sirt5-dependent manner. Collectively, the Set7/9-Sirt5 axis may be a promising epigenetic therapeutic target.
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Acknowledgements
The working model of this study was drawn using Biorender (www.biorender.com).
Funding
This work was supported by the Science and Technology Commission of Shanghai Municipality (22S11902700, 21S11907400), Shanghai Municipal Science and Technology Major Project (2023SHZDZX02), National Natural Science Foundation of China (82204386). National Key R&D Program of China (2020YFE0201600), Program of Shanghai Academic/Technology Research Leader (22XD1420100).
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WJH, ZYY, and TSB designed and performed the experiments, analyzed the data, and wrote the manuscript. XJ, LYH, CQW contributed to the manuscript. LXH, CJ, and DC designed the experiments, supervised the study, and revised the manuscript.
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Wang, J., Tan, S., Zhang, Y. et al. Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner. Cell Death Differ 31, 511–523 (2024). https://doi.org/10.1038/s41418-024-01264-y
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DOI: https://doi.org/10.1038/s41418-024-01264-y