KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells

Genes encoding the human beta-like hemoglobin proteins undergo a developmental switch from fetal gamma-globin to adult beta-globin expressionaroundthe time of birth. beta-hemoglobinopathies, such as sickle-cell disease and beta-thalassemia, result from mutations affecting the adult beta-globin gene. The only treatment options currently available carry significant adverse effects. Analyses of heritable variations in fetal hemoglobin (HbF) levels have provided evidence that reactivation of the silenced fetal gamma-globin genes in adult erythroid cells is a promising therapy. The gamma-globin repressor BCL11A has become the major focus, with several studies investigating its regulation and function as a first step to inhibiting its expression or activity. However, a second repression mechanism was recently shown to be mediated by the transcription factor ZBTB7A/LRF, suggesting that understanding the regulation of ZBTB7A may also be useful. Here we show that Kruppel-like factor 1 (KLF1) directly drives expression of ZBTB7A in erythroid cells by binding to its proximal promoter. We have also uncovered an erythroid-specific regulation mechanism, leading to the upregulation of a novel ZBTB7A transcript in the erythroid compartment. The demonstration that ZBTB7A, like BCL11A, is a KLF1 target gene also fits with the observation that reduced KLF1 expression or activity is associated with HbF derepression.