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

Cheng Zeng, Jiwei Chen, Emmalee W. Cooke, Arijita Subuddhi, Eliana T. Roodman, Fei Xavier Chen and Kaixiang Cao ()
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Cheng Zeng: 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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40606-1

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