Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced re-sponses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular al-terations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster -contain-ing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycol-ysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogram-ming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Automated summary

The lack of erythropoietin receptor leads to a deficiency of hemoglobin in CFU-E cells in embryos, along with massive iron overload in the fetal liver, indicating a communication issue between the liver and placenta. Additionally, the reduction of related proteins also causes a metabolic shift. Balancing interactions between erythropoiesis, iron homeostasis regulation, and metabolic reprogramming is crucial for survival.