GAS41 modulates ferroptosis by anchoring NRF2 on chromatin

Here, through genome-wide CRISPR-Cas9 screenings, we identified GAS41, a well-known histone reader as a major repressor for 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. Notably, 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 significantly to its oncogenic role in vivo. These data demonstrate that GAS41 is an important target for modulating tumor growth through ferroptosis. Our study reveals a previously unanticipated mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin and provides a model that the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac). Overall design: The CUT&RUN experiments were conducted in WT or GAS41 KO A549 cells. The commercial NRF2 antibody used CUT&RUN is purchased from Abcam (#62352)