KLF1 directly activates expression of the novel fetal globin repressor in erythroid cells.

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