Wu, D.; Li, Q.; Qiu, S.; Guo, C.; Li, F.; Shangguan, W.; Li, W.; Yang, D.; Meng, X.; Xing, M.; Chen, B.; Kong, L.; Huang, D. C. S.; Zhao, Q.

Decoding the molecular mechanisms underlying human fetal ({gamma}) globin gene silencing impacts therapeutic strategies for {beta}-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 {gamma}-globin gene in cultured erythroid cells, including those from {beta}-thalassemia patients. Conditional Fbl depletion in adult {beta}-YAC transgenic mice or in {beta}IVS-2-654-thalassemic mice reactivated the human {gamma}-globin gene or murine embryonic globin expression, respectively, which corrects hematologic and pathologic defects in {beta}-thalassemic mice. We showed that FBL plays a dual role in activating BCL11A expression and repressing {gamma}-globin gene expression, which is dependent on its histone methyltransferase activity. Our study may provide an alternative strategy for therapeutic targeted treatment of {beta}-hemoglobinopathies.