KLF1 regulates hemoglobin switching. (A-B) Absolute expression of MYB, BCL11A, SOX6, and KLF3 (in FPKM) during 5 stages of normal human erythroid cell differentiation from CD34⁺ cells compared with the proband. There is marked downregulation of SOX6 and KLF3 expression and moderate downregulation of BCL11A expression in the proband. (C) KLF1 occupies the human HBB gene promoter and 4 sites in the locus control region (LCR) that correspond to known DNase1 HS sites (K562 cells). KLF1 occupancy is greatest at HS2 and HS3. It does not occupy the HBE, HBG1, and HBG2 gene promoters in definitive erythroid cells. (D) KLF1 occupies the human HBA1 and HBA2 gene promoters and the HS sites at −40 kb (within the body of the NPRL3 gene) and further upstream. It does not bind the embryonically expressed HBAZ gene promoter in adult cells. HBM and HBQ are colored gray as they represent pseudogenes. (E) SOX6 expression is markedly reduced in KLF1-null erythroid cells (red RNA-seq track) compared with orthochromatic erythroblasts (green RNA-seq track). KLF1 occupies a site approximately 100 kb upstream of the most 5′ of the SOX6 exons (black track). This corresponds to a putative enhancer, as indicated by DNAse1 hypersensitivity in K562 cells (blue track). See Figure 5’s legend for explanation of the generation and coding of the custom tracks.