2. Academic Validation
  3. Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

  • Nat Commun. 2025 Jul 27;16(1):6919. doi: 10.1038/s41467-025-62177-z.
Henry W Bell # 1,  Ruopeng Feng # 2,  Manan Shah 1,  Yu Yao 2,  James Douglas 2,  Phillip A Doerfler 2 3,  Thiyagaraj Mayuranathan 2 4,  Michael F O'Dea 1,  Yichao Li 2,  Yong-Dong Wang 5,  Jingjing Zhang 2,  Joel P Mackay 6,  Yong Cheng 2,  Kate G R Quinlan 1,  Mitchell J Weiss # 7,  Merlin Crossley # 8
Affiliations

Affiliations

  • 1 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
  • 2 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Versiti Blood Research Institute, Milwaukee, WI, USA.
  • 4 Centre for Stem Cell Research (a Unit of inStem, Bengaluru), Christian Medical College Vellore Bagayam Campus, Vellore, India.
  • 5 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 6 School of Life and Environmental Sciences, University of Sydney, Darlington, NSW, Australia.
  • 7 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. mitch.weiss@stjude.org.
  • 8 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia. m.crossley@unsw.edu.au.
  • # Contributed equally.
PMID: 40715076 DOI: 10.1038/s41467-025-62177-z
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.

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