ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/081/SRR24049381/SRR24049381_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/082/SRR24049382/SRR24049382_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/084/SRR24049384/SRR24049384_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/079/SRR24049379/SRR24049379_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/082/SRR24049382/SRR24049382_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/081/SRR24049381/SRR24049381_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/083/SRR24049383/SRR24049383_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/080/SRR24049380/SRR24049380_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/079/SRR24049379/SRR24049379_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/084/SRR24049384/SRR24049384_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/083/SRR24049383/SRR24049383_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR240/080/SRR24049380/SRR24049380_1.fastq.gzprimaryOK200GenomicsHematology, St. Jude Children's Research Hospitalhttps://www.ebi.ac.uk/ena/browser/view/PRJNA951691Homo sapiensxref:PubMed:37400614Naturally occurring mutations in the γ-globin promoters can result in hereditary persistence of fetal hemoglobin (HPFH), a benign condition that ameliorates the severity of β-hemoglobinopathies through increased post-natal fetal hemoglobin (HbF) expression. Base editing to recreate the HPFH mutations is a promising approach to induce HbF. Compared with Cas9-generated indels, base-editing approaches were more potent, with the −175 A>G conversion resulting in the strongest induction of HbF by creating a new TAL1 binding motif that stimulates long-range interaction with the locus control region (LCR), a powerful upstream enhancer. Micro-Capture-C analysis showed that introducing the −175 A>G variant stimulated long-range interaction between the γ-globin promoters and the LCR in erythroid progenitor cell line. Together, these findings show that the −175 A>G variant creates a bipartite GATA–TAL1 motif, resulting in the assembly of a GATA1/TAL1/LMO2/LDB1 complex, which activates γ-globin gene transcription by enhancing its physical association with the LCR. Overall design: Micro-Capture-C experiments were performed in wild type hemizygous HUDEP-2 cells (HUDEP2∆εγδβ cells), HUDEP2∆εγδβ cells harboring -175 A>G mutation at -globin promoter the γ-globin promotesr (HBG2/HBG1). Wild type HUDEP-1 is used as a control.ENAfalseMicro-Capture-C to determine the long-range interaction of HBG1/2 promoter with the locus control region (LCR), a powerful upstream enhancer in -175 A>G mutantant HUDEP-2 cells.Micro-Capture-C to determine the long-range interaction of HBG1/2 promoter with the locus control region (LCR), a powerful upstream enhancer in -175 A>G mutantant HUDEP-2 cells.2025-09-242023-05-02PRJNA951691GSE228570960637400614