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

Abstract

Genes encoding the human β-like hemoglobin proteins undergo a developmental switch from fetal <i>γ-globin</i> to adult <i>β-globin</i> expression around the time of birth. β-hemoglobinopathies, such as sickle-cell disease and β-thalassemia, result from mutations affecting the adult <i>β-globin</i> 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 <i>γ-globin</i> genes in adult erythroid cells is a promising therapy. The <i>γ-globin</i> 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 Krüppel-like factor 1 (KLF1) directly drives expression of <i>ZBTB7A</i> 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 <i>ZBTB7A</i> transcript in the erythroid compartment. The demonstration that <i>ZBTB7A</i>, like <i>BCL11A</i>, is a KLF1 target gene also fits with the observation that reduced KLF1 expression or activity is associated with HbF derepression.