Figure 2.

Reversal of globin switching through Bcl11a gene editing. Genes c-Myb, KLF1, and Bcl11a positively regulate β-globin gene expression (light blue arrows). Klf1 also induces Bcl11a expression (light blue arrow). Bcl11a represses the expression of γ-globin (red line). Zinc-finger nuclease-mediated cleavage at a target sequence (blue) located in the DHS (DNAse hypersensitive site) +58 region generates DNA sequences that no longer contain a putative GATA1 transcription factor binding motif (in red). High frequency of those GATA1-less sequences in cell population is associated with reduced Bcl11a expression (red lines) and consequently higher γ-globin expression (sequence data from ref.⁷¹). Chr, chromosome; Ex, exon; LCR, locus-control region; HBE, ɛ-globin gene; HBG, γ-globin gene; HBD, δ-globin gene; HBB, β-globin gene; 3′ enh, 3′ enhancer; HbF, fetal hemoglobin; HbA, adult hemoglobin.