Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Hereditary persistence of fetal hemoglobin (HPFH) ameliorates beta-hemoglobinopathies by inhibiting the developmental switch from gamma-globin (HBG1/HBG2) to beta-globin (HBB) gene expression. Some forms of HPFH are associated with gamma-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain gamma-globin gene expression postnatally remains undefined. We mapped gamma-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce gamma-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate gamma-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing. Introduction of hereditary persistence of fetal hemoglobin variants into the gamma-globin promoter by using CRISPR mutagenesis and editing provides insights into transcription factor interplay, with implications for gene therapies targeting this element.

Automated summary

Hereditary persistence of fetal hemoglobin variants activate gamma-globin expression through distinct mechanisms involving transcription factors, providing insights for therapeutic genome editing and gene therapies targeting this element.