Reference - Detail
| RRC ID | 85385 |
|---|---|
| Author | Bell HW, Feng R, Shah M, Yao Y, Douglas J, Doerfler PA, Mayuranathan T, O'Dea MF, Li Y, Wang YD, Zhang J, Mackay JP, Cheng Y, Quinlan KGR, Weiss MJ, Crossley M. |
| Title | Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. |
| Journal | Nat Commun |
| 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. |
| Volume | 16(1) |
| Pages | 6919 |
| Published | 2025-7-27 |
| DOI | 10.1038/s41467-025-62177-z |
| PII | 10.1038/s41467-025-62177-z |
| PMID | 40715076 |
| PMC | PMC12297318 |
| MeSH | CCAAT-Enhancer-Binding Proteins / genetics CCAAT-Enhancer-Binding Proteins / metabolism CRISPR-Cas Systems Cell Line CpG Islands* / genetics DNA (Cytosine-5-)-Methyltransferase 1 / genetics DNA (Cytosine-5-)-Methyltransferase 1 / metabolism DNA Methylation* / genetics DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Epigenome* / genetics Epigenome Editing Gene Editing* / methods Gene Silencing* Humans Promoter Regions, Genetic* / genetics Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism gamma-Globins* / genetics gamma-Globins* / metabolism |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 52 |
| Altmetric score changes over past 6months | 10.0 |
| Resource | |
| Human and Animal Cells | HUDEP-2(RCB4557) |