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Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition

Author

Listed:
  • Cheng Zeng

    (Case Western Reserve University
    Case Western Reserve University)

  • Jiwei Chen

    (Institutes of Biomedical Sciences)

  • Emmalee W. Cooke

    (Case Western Reserve University)

  • Arijita Subuddhi

    (Case Western Reserve University)

  • Eliana T. Roodman

    (Case Western Reserve University)

  • Fei Xavier Chen

    (Institutes of Biomedical Sciences)

  • Kaixiang Cao

    (Case Western Reserve University
    Case Western Reserve University)

Abstract

The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 has a mild impact on gene expression and cellular differentiation whereas the loss of LSD1 protein de-represses enhancers globally and impairs cell fate transition. LSD1 deletion increases H3K27ac levels and P300 occupancy at LSD1-targeted enhancers. The gain of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into treating diseases driven by LSD1 mutations and misregulation.

Suggested Citation

  • Cheng Zeng & Jiwei Chen & Emmalee W. Cooke & Arijita Subuddhi & Eliana T. Roodman & Fei Xavier Chen & Kaixiang Cao, 2023. "Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40606-1
    DOI: 10.1038/s41467-023-40606-1
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    1. Fengqi Qiu & Peishan Jiang & Guiheng Zhang & Jie An & Kexin Ruan & Xiaowen Lyu & Jianya Zhou & Wanqiang Sheng, 2024. "Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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