Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells

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Abstract
The mechanisms by which the fetal-type β-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells remain a fundamental question in human biology and have therapeutic relevance to sickle cell disease and β-thalassemia. Here, we identify via a CRISPR–Cas9 genetic screen two members of the NFI transcription factor family—NFIA and NFIX—as HBG1/2 repressors. NFIA and NFIX are expressed at elevated levels in adult erythroid cells compared with fetal cells, and function cooperatively to repress HBG1/2 in cultured cells and in human-to-mouse xenotransplants. Genomic profiling, genome editing and DNA binding assays demonstrate that the potent concerted activity of NFIA and NFIX is explained in part by their ability to stimulate the expression of BCL11A, a known silencer of the HBG1/2 genes, and in part by directly repressing the HBG1/2 genes. Thus, NFI factors emerge as versatile regulators of the fetal-to-adult switch in β-globin production.
Funding Information
  • Pfizer
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL119479, HL007150-42, R01HL147879, R01HL156647)
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766, K08-DK129716, F32DK118822, R24DK106766, R24DK106766)
  • DiGaetano family;St Jude Children’s Research Hospital Collaborative Research Consortium on Novel Gene Therapies for Sickle Cell Disease
  • Doris Duke Charitable Foundation (#2020062)
  • American Society of Hematology
  • Cooley’s Anemia Foundation
  • Assisi Foundation of Memphis

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