H3K36 histone methyltransferase NSD3 functions as a multifaceted regulator of late erythropoiesis

Erythropoiesis, the red blood cell (RBC) formation process, is divided into early and late stages, each involving specific cellular and molecular events. Late erythropoiesis refers to the final stages of RBC formation, where erythroblasts undergo critical transformations to become mature erythrocytes. This process includes the basophilic erythroblast stage, where cells begin hemoglobin synthesis, followed by the polychromatic erythroblast stage, marked by increased hemoglobin and reduced RNA. In the orthochromatic erythroblast stage, cells synthesize hemoglobin, and enucleation occurs, producing reticulocytes that mature into red blood cells. The role of H3K36 histone methyltransferase NSD3 in regulating human erythropoiesis is still obscure. Therefore, the present study aimed to understand the role of NSD3 in late-stage erythropoiesis. We induced NSD3 knockdown on day 12 ex vivo differentiated erythroid cells using the lentiviral mediated knockdown approach. NSD3 knockdown leads to disrupted terminal erythroid differentiation with an abrupt increase in basophilic population and decreased ortho/poly chromatic erythroblasts. We also observed an altered gene expression of major erythroid specific genes associated with erythroid differentiation and maturation. Furthermore, we observed that the erythroid differentiation and maturation defects were accompanied by induced apoptosis and reduced proliferation upon NSD3 depletion, highlighting the multifaceted regulatory role of NSD3 during late erythropoiesis.