CircNFATc3 promotes Fetal Hemoglobin induction by regulating let-7b/GATA2 axis

Reactivation of developmentally suppressed fetal hemoglobin (HbF) holds therapeutic promise. However, the post-transcriptional control of regulators that orchestrate γ-globin (HBG1/2) expression is still elusive. This study aims to elucidate the highly understudied role of circular RNA (circRNA), circNFATc3, as post-transcriptional γ-globin regulator. This study evaluates the circNFATc3/let-7b/GATA2 axis and its relationship with HbF induction through computational and experimental molecular and cellular approaches, including gain and loss-of-function studies. These evaluations have revealed that competitive splicing of circNFATc3, at the expense of its linear transcript, sequesters let-7b miRNA, thereby reactivating GATA2-mediated HbF expression. Moreover, transcriptomic profiling of circNFATc3-overexpressed erythroid cells showed that its role is not only restricted to HbF induction but it may play a broader role in erythropoiesis, adding further complexity to the role of this circular transcript. Therefore, our study demonstrates a pivotal role of circNFATc3 as an HbF inducer and places this circRNA as a promising modifier in erythroid transcription programs, opening avenues for novel therapeutic strategies in β-thalassemia.