GAS41 modulates ferroptosis by anchoring NRF2 on chromatin

Zhe Wang, Xin Yang, Delin Chen, Yanqing Liu, Zhiming Li, Shoufu Duan, Zhiguo Zhang, Xuejun Jiang, Brent R. Stockwell and Wei Gu ()
Additional contact information
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
Xuejun Jiang: Memorial Sloan-Kettering Cancer Center
Brent R. Stockwell: Columbia University
Wei Gu: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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).

Date: 2024
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DOI: 10.1038/s41467-024-46857-w

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