DDIT4 promotes erythroid differentiation and coordinates with SIPA1 to regulate erythroid proliferation in bone marrow of high altitude erythrocytosis

Erythrocytosis moderately enhances the oxygen-carrying capacity of the blood and is considered a characteristic response of individuals adapting from low-altitude regions to high-altitude regions. Nevertheless, erythrocytosis can also turn excessive and result in maladaptive syndromes, such as high altitude polycythemia (HAPC). The increased differentiation or proliferation of erythroid cells in the bone marrow may be a crucial factor leading to accumulation of peripheral erythroid cells. However, the mechanism of erythroid regulation within the bone marrow of high-altitude erythrocytosis remains insufficiently systematically observed. We utilized single-cell transcription sequencing to characterize bone marrow cells following chronic hypoxic exposure and found that bone marrow erythrocytosis is associated with the accumulation of Baso-E, Poly-E, and Ortho-E cells at the terminal stage of erythroid lineage differentiation. Through analysis of differential gene expression and localization in differentiated cells within the erythroid lineage, we confirmed that DDIT4 expression was localized in advanced differentiated erythroblast including Baso-E, Poly-E and Ortho-E, its expression was significantly enhanced by hypoxia exposure. We demonstrated that overexpression of DDIT4 could promote K562 cell differentiation, and through the IP pull-down interaction protein profile, we found that DDIT4 might participate in regulating the cell cycle by interacting with SIPA1 to promote the proliferation of erythroid cells and may be involved in HAPC.