GAS41 modulates ferroptosis by anchoring NRF2 on chromatin

  • Nat Commun. 2024 Mar 21;15(1):2531. doi: 10.1038/s41467-024-46857-w.
Zhe Wang  #  1 ,  Xin Yang  #  1 ,  Delin Chen  1 ,  Yanqing Liu  1 ,  Zhiming Li  1 ,  Shoufu Duan  1 ,  Zhiguo Zhang  1  2  3  4 ,  Xuejun Jiang  5 ,  Brent R Stockwell  6  7 ,  Wei Gu  8  9  10
Affiliations
  • 1. Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 2. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 3. Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 4. Department of Genetics and Development, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 5. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 6. Department of Chemistry, Columbia University, New York, NY, USA.
  • 7. Department of Biological Sciences, Columbia University, New York, NY, USA.
  • 8. Institute for Cancer Genetics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA. [email protected].
  • 9. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA. [email protected].
  • 10. Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 38514704 DOI: 10.1038/s41467-024-46857-w
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).

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