Fibrillarin modulates fetal hemoglobin silencing

Decoding the molecular mechanisms underlying human fetal (γ) globin gene silencing impacts therapeutic strategies for β-thalassemia and sickle cell disease. Here, we identified a nucleolar protein, fibrillarin (FBL), which mediates the methylation of glutamine104 in histone H2A and functions as a repressor of the γ-globin gene in cultured erythroid cells, including those from β-thalassemia patients. Conditional Fbl depletion in adult β-YAC transgenic mice or in βIVS-2-654-thalassemic mice reactivated the human γ-globin gene or murine embryonic globin expression, respectively, which corrects hematologic and pathologic defects in β-thalassemic mice. We showed that FBL plays a dual role in activating BCL11A expression and repressing γ-globin gene expression, which is dependent on its histone methyltransferase activity. Our study may provide an alternative strategy for therapeutic targeted treatment of β-hemoglobinopathies.