ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR140/020/ERR14064620/ERR14064620.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR140/021/ERR14064621/ERR14064621.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR140/018/ERR14064618/ERR14064618.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR140/019/ERR14064619/ERR14064619.fastq.gzprimary200OKGenomicsImagine Institutehttps://www.ebi.ac.uk/ena/browser/view/PRJEB83576Beta-hemoglobinopathies are severe genetic diseases caused by mutations affecting the production of the adult β-globin chain. The clinical severity is mitigated by the co-inheritance of mutations that reactivate the production of the fetal β-like γ-globin in adults. However, the epigenetic mechanisms underlying the adult-to-fetal hemoglobin (HbA-to-HbF) switching are still not fully understood. Here, we used epigenome editing technologies to dissect the molecular mechanisms underlying γ- and β-globin gene regulation, and to develop novel potential therapeutics for β-hemoglobinopathies. Targeted removal of DNA methylation by dCas9-Tet1 (alone or together with the deposition of histone acetylation by CBP-dCas9) at the fetal promoters led to efficient and durable γ-globin reactivation, demonstrating that DNA methylation is a driver for HbF repression. This strategy, characterized by high specificity and a good safety profile, led to a substantial correction of the pathological phenotype in erythroid cells from patients with sickle cell disease.ENAfalseDissecting the epigenetic regulation of the fetal hemoglobin genes to unravel a novel therapeutic approach for β-hemoglobinopathiesDissecting the epigenetic regulation of the fetal hemoglobin genes to unravel a novel therapeutic approach for β-hemoglobinopathies2024-12-152024-12-15PRJEB83576