ArticleBlood2021
A natural DNMT1 mutation elevates the fetal hemoglobin level via epigenetic derepression of the γ-globin gene in β-thalassemia.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- New Gene Therapy Strategy for β-Thalassemia.Stem cell reviews and reports · 2026Review
- Circ_0001428 regulates erythropoiesis and γ-globin expression via activating the ATF4-BCL11A axis in β-thalassemia.Cellular and molecular life sciences : CMLS · 2026Article
- Efficacy and Safety of Thalidomidein Patients with Transfusion-Dependent B-Thalassemia: A Systematic Review, Meta-Analysis and GRADE Evaluation.Mediterranean journal of hematology and infectious diseases · 2026Review
- Comprehensive regulation of γ-globin expression by epigenetic modifications and protein post-translational modifications.Clinical epigenetics · 2025Review
- Removal of promoter CpG methylation by epigenome editing reverses HBG silencing.Nature communications · 2025Article
- A common TBP-binding site mutation elevates fetal hemoglobin levels by competitive globin switching change in β-thalassemia.Blood advances · 2025Article
- Dissecting the epigenetic regulation of the fetal hemoglobin genes to unravel a novel therapeutic approach for β-hemoglobinopathies.Nucleic acids research · 2025Article
- The epigenetic revolution in hematology: from benchside breakthroughs to clinical transformations.Clinical and experimental medicine · 2025Review
- A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.Human molecular genetics · 2025Article
- Rapid detection of genetic modifiers of β-thalassemia based on MALDI-TOF MS.Annals of hematology · 2025Article
- Exploring Novel Strategies to Alleviate Symptoms of β-Globinopathies: Examining the Potential Role of Embryonic ε-globin Induction.Transfusion medicine reviews · 2024Review
- Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in hematological diseases.Molecular medicine (Cambridge, Mass.) · 2024Review
- Review
- DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner.Cell death and differentiation · 2024Article
- Prognostic Value of Pretreatment Fetal Hemoglobin Levels in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia Treated with Azacitidine: A Single-center Retrospective Study.Internal medicine (Tokyo, Japan) · 2024Article
- Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.Cytometry. Part B, Clinical cytometry · 2024Article
- CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia.Human genetics · 2023Review
- Article
- A Porcine DNMT1 Variant: Molecular Cloning and Generation of Specific Polyclonal Antibody.Genes · 2023Article
- Negative regulation ofTranslational pediatrics · 2023Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator of the formation of large macromolecular complexes that repress human γ-globin expression by maintaining DNA methylation. However, very little is known about the association of DNMT1 variants with β-thalassemia phenotypes. We systematically investigated associations between variants in DNMT1 and phenotypes in 1142 β-thalassemia subjects and identified a novel missense mutation (c.2633G>A, S878F) in the DNMT1 bromo-adjacent homology-1 (BAH1) domain. We functionally characterized this mutation in CD34+ cells from patients and engineered HuDEP-2 mutant cells. Our results demonstrate that DNMT1 phosphorylation is abrogated by substituting serine with phenylalanine at position 878, resulting in lower stability and catalytic activity loss. S878F mutation also attenuated DNMT1 interactions with BCL11A, GATA1, and HDAC1/2, and reduced recruitment of DNMT1 to the γ-globin (HBG) promoters, leading to epigenetic derepression of γ-globin expression. By analyzing the F-cell pattern, we demonstrated that the effect of DNMT1 mutation on increased fetal hemoglobin (HbF) is heterocellular. Furthermore, introduction of S878F mutation into erythroid cells by clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) recapitulated γ-globin reactivation. Thus, the natural S878F DNMT1 mutation is a novel modulator of HbF synthesis and represents a potential new therapeutic target for β-hemoglobinopathies.
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