ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 9 citations in OpenAlex.
- miRNA-Mediated Regulation of γ-Globin to β-Globin Switching: Therapeutic Potential in β-Hemoglobinopathies.International journal of molecular sciences · 2026Review
- Novel LRF/ZBTB7A variants and known HbF-modulating SNPs in transfusion-dependent β-thalassemia.BMC medical genomics · 2025Article
- Gene Therapy of Beta Hemoglobinopathies.Biomedicines · 2025Review
- Characterization and risk assessment of HbF elevation in non-thalassemia hematologic disease patients in Guangdong region.Annals of hematology · 2025Article
- Review
- Short Stature and Developmental Delay Associated With a Novel Frame-Shift Mutation in ZNF292: Case Report and Literature Review.Clinical case reports · 2025Article
- BCL11A-deficient human erythropoiesis is impaired in vitro and after xenotransplantation into mice.Blood advances · 2025Article
- Solution structure of the Z0 domain from transcription repressor BCL11A sheds light on the sequence properties of protein-binding zinc fingers.Protein science : a publication of the Protein Society · 2025Article
- Nonclinical evaluation of HBG1/2 and BCL11A as genome-editing targets for the treatment of β-hemoglobinopathies.Blood advances · 2025Article
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Authors and funding
27 authors at 7 institutions in 4 countries.
Funding
Abstract
BCL11A-XL directly binds and represses the fetal globin (HBG1/2) gene promoters, using 3 zinc-finger domains (ZnF4, ZnF5, and ZnF6), and is a potential target for β-hemoglobinopathy treatments. Disrupting BCL11A-XL results in derepression of fetal globin and high HbF, but also affects hematopoietic stem and progenitor cell (HSPC) engraftment and erythroid maturation. Intriguingly, neurodevelopmental patients with ZnF domain mutations have elevated HbF with normal hematological parameters. Inspired by this natural phenomenon, we used both CRISPR-Cas9 and base editing at specific ZnF domains and assessed the impacts on HbF production and hematopoietic differentiation. Generating indels in the various ZnF domains by CRISPR-Cas9 prevented the binding of BCL11A-XL to its site in the HBG1/2 promoters and elevated the HbF levels but affected normal hematopoiesis. Far fewer side effects were observed with base editing- for instance, erythroid maturation in vitro was near normal. However, we observed a modest reduction in HSPC engraftment and a complete loss of B cell development in vivo, presumably because current base editing is not capable of precisely recapitulating the mutations found in patients with BCL11A-XL-associated neurodevelopment disorders. Overall, our results reveal that disrupting different ZnF domains has different effects. Disrupting ZnF4 elevated HbF levels significantly while leaving many other erythroid target genes unaffected, and interestingly, disrupting ZnF6 also elevated HbF levels, which was unexpected because this region does not directly interact with the HBG1/2 promoters. This first structure/function analysis of ZnF4-6 provides important insights into the domains of BCL11A-XL that are required to repress fetal globin expression and provide framework for exploring the introduction of natural mutations that may enable the derepression of single gene while leaving other functions unaffected.
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