Journal
NATURE GENETICS
Volume 53, Issue 8, Pages 1177-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-021-00904-0
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Funding
- National Institutes of Health (NIH) [P01HL053749, R01HL156647, R35GM133614, R24106766, F32DK118822]
- Assisi Foundation of Memphis
- Doris Duke Charitable Foundation [2017093]
- Australian Government Research Training Program Scholarship
- Australian National Health and Medical Research Council [APP1164920]
- St. Jude Collaborative Research Consortium for Sickle Cell Disease
- NIH [P30CA21765]
- St. Jude/ALSAC
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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.
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.
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