The N6-methyladenosine methyltransferase wtap maintains erythropoiesis by stabilizing STAT5a mRNA

Abstract

Abstract Anemia, a common global health problem, affects about more than 500 million people worldwide. N6-methyladenosine (m6A) methylation is the most common epigenetic modification of mRNA with the increasingly essential role in normal or abnormal hematopoiesis. However, the functions of m6A in the normal hematopoiesis remain elusive, particularly in erythropoiesis. Here, we report WTAP, a critical component of m6A methyltransferase complex, is highly expressed in erythroid progenitor cells, and is downregulated during erythroid differentiation. WTAP depletion disrupts the erythropoiesis by reducing erythroid progenitors, promoting apoptosis of erythroblasts, and affecting the heme biosynthetic process. Mechanistically, WTAP exerts its role in erythropoiesis by controlling the m6A modified sites of its target mRNA transcript Stat5a. Collectively, our study uncovers that WTAP and STAT5a plays an essential regulatory machinery to maintain erythropoiesis, and highlight its pivotal roles and m6A modification in erythropoiesis.