1. GAS41 modulates ferroptosis by anchoring NRF2 on chromatin.
- Author
-
Wang Z, Yang X, Chen D, Liu Y, Li Z, Duan S, Zhang Z, Jiang X, Stockwell BR, and Gu W
- Subjects
- Chromatin genetics, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Oncogenes, Histones metabolism, Ferroptosis genetics
- 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)., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF