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

Autor: Zeng C; Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.; Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA., Chen J; Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Shanghai, China., Cooke EW; Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA., Subuddhi A; Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA., Roodman ET; Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA., Chen FX; Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Shanghai, China., Cao K; Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. kxc725@case.edu.; Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. kxc725@case.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Aug 22; Vol. 14 (1), pp. 4944. Date of Electronic Publication: 2023 Aug 22.
DOI: 10.1038/s41467-023-40606-1
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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