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Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner

Cell Death & Differentiation volume 31, pages 511–523 (2024)Cite this article

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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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Fig. 1: Set7/9 KO mice are protected from severe deficits after stroke.
Fig. 2: Blocking Set7/9 protects the neuron from OGD/R damage.
Fig. 3: Regulation of glutamine metabolism by Sirt5 is involved in Set7/9-mediated ischemic brain insult.
Fig. 4: Blocking Set7/9 mediated neuroprotection is largely Sirt5-dependent.
Fig. 5: Reducing Sirt5 restores susceptibility of Set7/9 KO mice.
Fig. 6: Proteomic Profiling of HT22 cells with Set7/9 knockdown.
Fig. 7: Set7/9 inhibits Sirt5 transcription through the transcriptional inhibition complex, Cbx1/Suv39h1/H3K9me2/3.
Fig. 8: Working model of Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner.

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Data availability

All data in this study are provided in the paper and Supplementary Materials.

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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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  1. These authors contributed equally: Jinghuan Wang, Subei Tan.

Authors and Affiliations

  1. Shanghai Key Labortary of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai, 201203, China

    Jinghuan Wang, Subei Tan, Yuyu Zhang, Jie Xu, Yuhui Li, Qianwen Cheng, Xinhua Liu & Jun Chang

  2. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 201203, China

    Subei Tan & Chen Ding

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Contributions

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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Correspondence to Chen Ding, Xinhua Liu or Jun Chang.

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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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