108: Epigenome Editing Reverses HBG Silencing

️ Episode 108: Epigenome Editing Reverses HBG Silencing In this episode of PaperCast Base by Base, we explore how targeted removal of CpG methylation at the HBG promoters causally reactivates fetal hemoglobin (HbF) without cutting DNA, revealing a precise path to treat β‑hemoglobinopathies. Study Highlights:A forward CRISPR screen in adult‑type erythroid cells (HUDEP2) pinpointed UHRF1, a DNMT1 cofactor, as a mediator of HBG repression; its disruption globally reduced CpG methylation and increased HbF, and promoter re‑methylation with dCas9‑DNMT3A/3L restored silencing. Targeted demethylation using a dCas9‑TET1 editor at six guides produced localized promoter demethylation and strong γ‑globin activation—raising HBG/(HBG+HBB) up to ~86%—with expression sustained for months in culture. In primary CD34+ cell‑derived erythroblasts, the same promoter‑focused demethylation increased HBG mRNA and HbF without altering maturation markers, and chromatin profiling showed higher accessibility and activating histone marks while BCL11A occupancy persisted. Induction correlated with combined demethylation across multiple CpGs upstream of the TSS rather than any single site, and introducing a methyl‑CpG‑binding‑deficient MBD2 mutant mimicked activation, supporting a model in which CpG methylation recruits MBD2‑NuRD to enforce silencing. Conclusion:Targeted epigenome editing of CpG methylation at HBG offers a DNA‑break‑free avenue for durable HbF induction in β‑hemoglobinopathies. Reference:Bell HW, Feng R, Shah M, Yao Y, Douglas J, Doerfler PA, Mayuranathan T, O’Dea MF, Li Y, Wang Y‑D, Zhang J, Mackay JP, Cheng Y, Quinlan KGR, Weiss MJ, Crossley M. Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nature Communications. 2025;16:6919. https://doi.org/10.1038/s41467-025-62177-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ HBG promoter; CpG methylation; epigenome editing; fetal hemoglobin (HbF); MBD2–NuRD

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