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GAS41 modulates ferroptosis by anchoring NRF2 on chromatin

Author

Listed:
  • Zhe Wang

    (Columbia University)

  • Xin Yang

    (Columbia University)

  • Delin Chen

    (Columbia University)

  • Yanqing Liu

    (Columbia University)

  • Zhiming Li

    (Columbia University)

  • Shoufu Duan

    (Columbia University)

  • Zhiguo Zhang

    (Columbia University
    Columbia University
    Columbia University
    Columbia University)

  • Xuejun Jiang

    (Memorial Sloan-Kettering Cancer Center)

  • Brent R. Stockwell

    (Columbia University
    Columbia University)

  • Wei Gu

    (Columbia University
    Columbia University
    Columbia University)

Abstract

YEATS domain-containing protein GAS41 is a histone reader and oncogene. Here, through genome-wide CRISPR-Cas9 screenings, we identify GAS41 as a repressor of ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter, independent of NRF2 binding. By bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes to its oncogenic role in vivo. These data demonstrate that GAS41 is a target for modulating tumor growth through ferroptosis. Our study reveals a mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin, and provides a model in which the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac).

Suggested Citation

  • Zhe Wang & Xin Yang & Delin Chen & Yanqing Liu & Zhiming Li & Shoufu Duan & Zhiguo Zhang & Xuejun Jiang & Brent R. Stockwell & Wei Gu, 2024. "GAS41 modulates ferroptosis by anchoring NRF2 on chromatin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46857-w
    DOI: 10.1038/s41467-024-46857-w
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