Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

作者：Henry W. Bell, Ruopeng Feng, Manan Shah, Yu Yao, James Joshua Douglas, Phillip A. Doerfler, Thiyagaraj Mayuranathan, Michael F O'Dea, Yichao Li, Yong‐Dong Wang, Jingjing Zhang, Joel P. Mackay, Yong Cheng, Kate Quinlan, Mitchell J. Weiss, Merlin Crossley · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62177-z · 被引用次数：8 · 研究领域：Epigenetics and DNA Methylation、Hemoglobinopathies and Related Disorders、HIV Research and Treatment

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.