Activation of -globin expression by LncRNA-mediated ERF promoter hypermethylation in -thalassemia

The mechanism that drives the switch from fetal to adult hemoglobin (Hb) provides a therapeutic target for beta-thalassemia. We have previously identified that hypermethylation of transcription factor ERF promoter reactivated gamma-globin expression. To uncover the mechanism underlying the hypermethylation of ERF promoter, we performed RNA sequencing in beta(0)/beta(0)-thalassemia patients and identified an upregulated long noncoding RNA (RP11-196G18.23) associated with HbF production. RP11-196G18.23 bound to the ERF promoter and recruited DNA methyltransferase 3A to promote DNA hypermethylation-mediated ERF downregulation, thereby ameliorating ERF-induced gamma-globin inactivation. The identification of RP11-196G18.23 provides an epigenetic mechanism for the reactivation of fetal gamma-globin expression for beta-hemoglobinopathies.