Structural insights into the recognition of γ-globin gene promoter by BCL11A

Dear Editor,

Rare genetic variations that lead to substantial elevations of HbF in HPFH are located ~115 bp (referred to as the γ-globin −115 HPFH region) (Fig. 1a) and ~200 bp upstream of the transcription start sites of the duplicated γ-globin genes.^1,3 The variations located in the γ-globin −115 HPFH region include single base substitutions at −117 (G−117A) and −114 (C−114A/T/G) or a 13-bp deletion (Fig. 1a).^4,5,6,7,8 Furthermore, genome-wide association studies (GWAS) of HPFH identified the transcription factor B-cell lymphoma/leukemia 11A (BCL11A) as the major HbF silencer (Fig. 1a);^9,10 however, the mechanism by which BCL11A represses γ-globin expression has not been fully elucidated. Recently, two groups independently reported that BCL11A directly binds to the γ-globin −115 HPFH region through its C-terminal three tandem C2H2 zinc fingers (Znf4-6),^11,12 establishing a direct link between BCL11A and the γ-globin gene promoters.

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