Regulation of N⁶-methyladenosine modification in erythropoiesis and thalassemia

In eukaryotic RNA, N⁶-methyladenosine (m⁶A) is a prevalent form of methylation modification. The m⁶A modification process is reversible and dynamic, written by m⁶A methyltransferase complex, erased by m⁶A demethylase, and recognized by m⁶A binding proteins. Through mediating RNA stability, decay, alternative splicing, and translation processes, m⁶A modification regulates gene expression at the post-transcriptional level. Erythropoiesis is the process of hematopoietic stem cells undergoing proliferation, a series of differentiation and maturation to form red blood cells (RBCs). Thalassemia is a common monogenic disease characterized by excessive production of ineffective RBCs in the peripheral circulation, resulting in hemolytic anemia. Increasing evidence suggests that m⁶A modification plays a crucial role in erythropoiesis. In this review, we comprehensively summarize the function of m⁶A modification in erythropoiesis and further generalize the mechanism of m⁶A modification regulating ineffective erythropoiesis and fetal hemoglobin expression. The purpose is to improve the understanding of the pathogenesis of erythroid dysplasia and offer new perspectives for the diagnosis and treatment of thalassemia.