APA
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Bell, H. W., Feng, R., Shah, M., Yao, Y., Douglas, J., Doerfler, P. A., … Crossley, M. (2025). Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nature Communications.
Chicago/Turabian
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Bell, Henry W., Ruopeng Feng, Manan Shah, Yu Yao, James Douglas, Phillip A. Doerfler, Thiyagaraj Mayuranathan, et al. “Removal of Promoter CpG Methylation by Epigenome Editing Reverses HBG Silencing.” Nature Communications (2025).
MLA
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Bell, Henry W., et al. “Removal of Promoter CpG Methylation by Epigenome Editing Reverses HBG Silencing.” Nature Communications, 2025.
BibTeX Click to copy
@article{henry2025a,
title = {Removal of promoter CpG methylation by epigenome editing reverses HBG silencing},
year = {2025},
journal = {Nature Communications},
author = {Bell, Henry W. and Feng, Ruopeng and Shah, Manan and Yao, Yu and Douglas, James and Doerfler, Phillip A. and Mayuranathan, Thiyagaraj and O'Dea, Michael F and Li, Yichao and Wang, Yong-Dong and Zhang, Jingjing and Mackay, Joel P. and Cheng, Yong and Quinlan, K. and Weiss, Mitchell J and Crossley, M.}
}
β-hemoglobinopathies caused by mutations in adult-expressed HBB can be treated by re-activating the adjacent paralogous genes HBG1 and HBG2 (HBG), which are normally silenced perinatally. Although HBG expression is induced by global demethylating drugs, their mechanism is poorly understood, and toxicity limits their use. We identify the DNMT1-associated maintenance methylation protein UHRF1 as a mediator of HBG repression through a CRISPR/Cas9 screen. Loss of UHRF1 in the adult-type erythroid cell line HUDEP2 causes global demethylation and HBG activation that is reversed upon localized promoter re-methylation. Conversely, targeted demethylation of the HBG promoters activates their genes in HUDEP2 or primary CD34+ cell-derived erythroblasts. Mutation of MBD2, a CpG-methylation reading component of the NuRD co-repressor complex, recapitulates the effects of promoter demethylation. Our findings demonstrate that localized CpGmethylation at the HBG promoters facilitates gene silencing and identify a potential therapeutic approach for β-hemoglobinopathies via epigenomic editing.