Activating transcription factor 4 in erythroid development and -thalassemia: a powerful regulator with therapeutic...

Activating transcription factor 4 (ATF4) is a fundamental basic region/leucine zipper transcription factor, responds to various stress signals, and plays crucial roles in normal metabolic and stress response processes. Although its functions in human health and disease are not completely understood, compelling evidence underscores ATF4 is indispensable for multiple stages and lineages of erythroid development, including the regulation of fetal liver hematopoietic stem cells, induction of terminal erythroid differentiation, and maintenance of erythroid homeostasis. $$ -Thalassemia is a blood disorder arising from mutations in the $$ -globin gene. Reactivating the expression of the $$ -globin gene in adult patients has emerged as a promising therapeutic strategy for ameliorating clinical symptoms associated with $$ -thalassemia. Recent research has suggested that ATF4 contributes to decreased fetal hemoglobin (HbF) level through its binding to potent negative regulators of HbF, such as BCL11A and MYB. Notably, evidence also suggests a contrasting outcome where increased ATF4 protein levels are associated with enhanced HbF at the transcriptional level. Consequently, the identification of mechanisms that modulate ATF4-mediated $$ -globin transcription and its effects on erythroid development may unveil novel targets for $$ -thalassemia treatment.