Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

Henry W. Bell, Ruopeng Feng, Manan Shah, Yu Yao, James Douglas, Phillip A. Doerfler, Thiyagaraj Mayuranathan, Michael F. O’Dea, Yichao Li, Yong-Dong Wang, Jingjing Zhang, Joel P. Mackay, Yong Cheng, Kate G. R. Quinlan, Mitchell J. Weiss () and Merlin Crossley ()
Additional contact information
Henry W. Bell: University of New South Wales
Ruopeng Feng: St. Jude Children’s Research Hospital
Manan Shah: University of New South Wales
Yu Yao: St. Jude Children’s Research Hospital
James Douglas: St. Jude Children’s Research Hospital
Phillip A. Doerfler: St. Jude Children’s Research Hospital
Thiyagaraj Mayuranathan: St. Jude Children’s Research Hospital
Michael F. O’Dea: University of New South Wales
Yichao Li: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Jingjing Zhang: St. Jude Children’s Research Hospital
Joel P. Mackay: University of Sydney
Yong Cheng: St. Jude Children’s Research Hospital
Kate G. R. Quinlan: University of New South Wales
Mitchell J. Weiss: St. Jude Children’s Research Hospital
Merlin Crossley: University of New South Wales

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62177-z

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