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Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

Author

Listed:
  • 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
    Versiti Blood Research Institute)

  • Thiyagaraj Mayuranathan

    (St. Jude Children’s Research Hospital
    Christian Medical College Vellore Bagayam Campus)

  • 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)

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.

Suggested Citation

  • 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 & Y, 2025. "Removal of promoter CpG methylation by epigenome editing reverses HBG silencing," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62177-z
    DOI: 10.1038/s41467-025-62177-z
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