biostudies-literatureRajendiran VScience and Engineering Research BoardIndia Ministry of Science & Technology Department of BiotechnologyIndian Council of Medical ResearchDBT/Wellcome Trust India AllianceAustralian Medical Council663-677https://www.ebi.ac.uk/biostudies/studies/S-EPMC10928131biostudies-literatureUnknown32(3)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 promMolecular therapy : the journal of the American Society of Gene TherapyBase editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.PMC10928131IA/TSG/22/1/600410Periyasami YPai AAPaul JRajendiran VMarepally SMackay JPGeorge ARamalingam RHaddad MCrossley MPrasad KSrivastava AVelayudhan SRGopalakrishnan CRavi NSMohankumar KMAriudainambi KMahalingam GBalasubramanian PWyman SDevaraju NGopinathan SThangavel SPanigrahi LNakamura YCorn JESukumaran DfalseBase editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.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 prom2024-01-01T00:00:00Z2024 Mar2026-04-08T19:50:31.051Z2025-04-04T00:12:11.362ZS-EPMC109281313827365410.1016/j.ymthe.2024.01.023