The protective role of TET2 in erythroid iron homeostasis against oxidative stress and erythropoiesis.

Although previous studies suggested that stress erythropoiesis and iron metabolism regulate each other to increase iron availability for hemoglobin synthesis, the molecular bases determining its different traits remain elusive. In addition, global DNA demethylation has been reported during mouse erythropoiesis in vivo. However, the understanding of iron-related genes through DNA demethylation under stress erythropoiesis is largely unknown. In the current study, we found disordered iron homeostasis and misregulated hepcidin-ferroportin axis under stress erythropoiesis. Interestingly, global 5hmC content and TET2 expression were significantly induced by oxidative stress, whereas antioxidant had the opposite's effect. Mechanistic investigation manifested that TET2-mediated DNA demethylation promotes the expression of ferroportin and erythroferrone against oxidative stress. Besides, the expression of NRF2 was significantly increased by TET2-mediated DNA demethylation during stress erythropoiesis. Elevated NRF2 expression could also modulate the activation of ferroportin and erythroferrone through a canonical antioxidant response element within its promoter. These direct and indirect pathways of TET2 synergistically cooperated to mediating iron metabolism during stress erythropoiesis. Our work revealed a critical role of TET2-mediated DNA demethylation against oxidative stress, and provided the molecular mechanisms underlying the epigenetic regulation of iron homeostasis in response to stress erythropoiesis.