Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin

Abstract

The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.

Figure 1. The BCL11A–HbF repression axis

BCL11A itself relies on an erythroid enhancer, the subject of common trait-associated genetic variation, for its adult-stage erythroid expression pattern. GATA1 and TAL1 bind to this enhancer, and KLF1 (which may in turn be regulated by MYB) transactivates BCL11A, binding to its promoter. BCL11A is found in a multiprotein transcriptional complex in erythroid precursors, including chromatin regulators such as the NuRD complex (with Mi2β helicase and HDAC1/2 deacetylases), DNMT1 DNA methyltransferase, LSD1 lysine demethylase, SWI/SNF remodeling complex, additional corepressors such as NCoR and BCoR, and erythroid DNA-binding transcription factors such as GATA1, IKZF1, Runx1, and Sox6. BCL11A binds various regions of the β-globin gene cluster, including the locus control region (LCR) distal enhancer elements, to the ε-globin gene itself, and to intergenic sequences between γ- and δ-globin that have been implicated in γ-globin repression. BCL11A does not bind directly to the γ-globin genes. The outcome of BCL11A expression in adult-stage erythroid cells is the predominant expression of β-globin (and thus HbA) at the expense of γ-globin (and HbF).

Figure 2. Therapeutic genome editing of BCL11A for the β-hemoglobin disorders

Hematopoietic stem cells may be collected from a β-hemoglobin disorder patient, modified ex vivo, and then autologously re-engrafted to the patient. Genome editing technology has been rapidly advancing, and a variety of targetable endonucleases, such as CRISPR/Cas9, could be employed. The target sequences could be the erythroid enhancer of BCL11A. This strategies would allow disruption of BCL11A's repression of HbF in erythroid cells while sparing extra-erythroid functions of BCL11A. Furthermore, this genetic disruption would rely on the robust nonhomologous end-joining repair pathway, rather than on lower-frequency homology-directed repair.