KLF1 regulates BCL11A expression and γ- to β-globin gene switching

Abstract

We show that knockdown of KLF1 in human and mouse adult erythroid progenitors markedly reduces BCL11A levels and increases human gamma-globin/beta-globin expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. Controlled knockdown of KLF1 in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with beta-thalassemia or sickle cell disease.

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

“…KLF1 (or EKLF) is a critical erythroid regulator required for adult β-globin transcription (11). Recently it was shown that KLF1 occupies the BCL11A promoter and activates its expression (12,13). Consistent with previous analysis, knockdown of BCL11A or KLF1 results in marked increase in γ-globin expression and serves as positive controls for the RNAi screen.…”

BCL11Acontrôle l’expression de l’hémoglobine fœtale

“…L'étude en a été faite sur la souris « Berkeley » SCD (sickle cell disease) dont le phénotype récapitule bien la maladie drépanocytaire : ané-mie, augmentation des réticulocytes, taux d'HbF bas, durée de vie des globules rouges abrégée. L'introduction d'allèles BCL11A-nul chez cette souris (SCD Bcl11a fl/fl EpoR-Cre + ) corrige ces altérations et restaure un phénotype très voisin de celui de souris témoins d'HbF (HPFH) [8], et simultanément dans un travail expérimental chez la souris [9]. L'action de KLF1 s'exercerait indirectement par une régulation d'expression de BCL11A.…”

Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

“…The role of KLF1 and BCL11A in the switching of fetal to adult b-like globin gene expression is of particular interest. 13,14 Since mice do not have a fetal b-like globin gene, we used animals carrying a human b-globin locus transgene (line PAC8. 1 7 ) to investigate this.…”

“…11 In contrast, it was recently shown that KLF1 activates BCL11A expression. 13,14 KLF1 has a critical role in erythroid development, and in mice, its expression increases threefold upon the transition from primitive to definitive erythropoiesis. 15 Analysis of Klf1 knockout embryos revealed lethality at E14.5 due to anemia caused by disrupted fetal liver erythropoiesis.…”

“…13 Analysis of the HPFH phenotype has led to the proposal that KLF1 has a dual role in g-globin suppression through its preferential activation of the b-globin gene and as a key activator of expression of the BCL11A repressor protein. 13,14 Here, we used mice carrying a human b-globin locus transgene (PAC8.1) 7 and crossed them with mice carrying Klf1 knockout, 16 Bcl11a floxed, and EpoR Cre knockin 24 alleles to interrogate the impact of these two key molecules, KLF1 and BCL11A, on erythropoiesis and globin gene regulation.…”