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

Sajib Chakraborty; Geoffroy Andrieux; Philipp Kastl; Lorenz Adlung; Sandro Altamura; Martin E. Boehm; Luisa E. Schwarzmüller; Yomn Abdullah; Marie Christine Wagner; Barbara Helm; Hermann Josef Gröne; Wolf D. Lehmann; Melanie Boerries; Hauke Busch; Martina U. Muckenthaler; Marcel Schilling; Ursula Klingmüller

doi:10.1016/j.celrep.2022.111360

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

Sajib Chakraborty, Geoffroy Andrieux, Philipp Kastl, Lorenz Adlung, Sandro Altamura, Martin E. Boehm, Luisa E. Schwarzmüller, Yomn Abdullah, Marie Christine Wagner, Barbara Helm, Hermann Josef Gröne, Wolf D. Lehmann, Melanie Boerries^*, Hauke Busch^*, Martina U. Muckenthaler^*, Marcel Schilling^*, Ursula Klingmüller^*

^*Corresponding author for this work

1 Citation (Scopus)

Abstract

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 responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations 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-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Original language	English
Article number	111360
Journal	Cell Reports
Volume	40
Issue number	12
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2022.111360
Publication status	Published - 20.09.2022

Funding

We thank Susen Lippmann, Alexander Held, and Marvin Wäsch for excellent technical assistance. We thank Tonmoy Das for assisting in the illustrations and graphical design. We acknowledge support from the German Federal Ministry of Education and Research ( BMBF ) within the e:Bio collaborative research project Systems Biology of Erythropoietin (SBEpo; S.C., L.A., M.S., U.K., G.A., H.B., and M.B.), the framework of the e:Med research and funding concept (M.B.), the German Center for Lung Research (DZL; M.E.B., M.U.M., and U.K.), the Medical Informatics Funding Scheme MIRACUM-FKZ 01ZZ1801B (M.B.), EkoEstMed-FKZ 01ZZ2015 (G.A.), the LiSyM network (U.K.), the LiSyM-Cancer networks SMART-NAFLD (U.K.) and C-TIP-HCC (U.K.), and the MSCoreSys network SMART-CARE (B.H. and U.K.). We also acknowledge support from the Deutsche Forschungsgemeinschaft ( DFG ) within the Cluster of Excellence 306 Inflammation at Interfaces (H.B.), the CRC1453 (Project ID 431984000-S1, M.B.), CRC1160 (Z02, M.B.), TRR 167 (Z01, M.B.), SFB 1118 (M.U.M.), FerrOs – FOR5146 (M.U.M., S.A., P.K., and U.K.), and SPP2306 (M.U.M.). We further acknowledge support from the Helmholtz International Graduate School for Cancer Research at the German Cancer Research Center ( DKFZ ) (S.C. and L.A.), the Deutscher Akademischer Austauschdienst (A New Passage to India; M.U.M.), and the Dietmar Hopp foundation (M.U.M.).

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Chakraborty, S., Andrieux, G., Kastl, P., Adlung, L., Altamura, S., Boehm, M. E., Schwarzmüller, L. E., Abdullah, Y., Wagner, M. C., Helm, B., Gröne, H. J., Lehmann, W. D., Boerries, M., Busch, H., Muckenthaler, M. U., Schilling, M., & Klingmüller, U. (2022). Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo. Cell Reports, 40(12), Article 111360. https://doi.org/10.1016/j.celrep.2022.111360

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title = "Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo",

abstract = "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 responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations 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-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.",

author = "Sajib Chakraborty and Geoffroy Andrieux and Philipp Kastl and Lorenz Adlung and Sandro Altamura and Boehm, \{Martin E.\} and Schwarzm{\"u}ller, \{Luisa E.\} and Yomn Abdullah and Wagner, \{Marie Christine\} and Barbara Helm and Gr{\"o}ne, \{Hermann Josef\} and Lehmann, \{Wolf D.\} and Melanie Boerries and Hauke Busch and Muckenthaler, \{Martina U.\} and Marcel Schilling and Ursula Klingm{\"u}ller",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

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doi = "10.1016/j.celrep.2022.111360",

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Chakraborty, S, Andrieux, G, Kastl, P, Adlung, L, Altamura, S, Boehm, ME, Schwarzmüller, LE, Abdullah, Y, Wagner, MC, Helm, B, Gröne, HJ, Lehmann, WD, Boerries, M, Busch, H, Muckenthaler, MU, Schilling, M & Klingmüller, U 2022, 'Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo', Cell Reports, vol. 40, no. 12, 111360. https://doi.org/10.1016/j.celrep.2022.111360

TY - JOUR

T1 - Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo

AU - Chakraborty, Sajib

AU - Andrieux, Geoffroy

AU - Kastl, Philipp

AU - Adlung, Lorenz

AU - Altamura, Sandro

AU - Boehm, Martin E.

AU - Schwarzmüller, Luisa E.

AU - Abdullah, Yomn

AU - Wagner, Marie Christine

AU - Helm, Barbara

AU - Gröne, Hermann Josef

AU - Lehmann, Wolf D.

AU - Boerries, Melanie

AU - Busch, Hauke

AU - Muckenthaler, Martina U.

AU - Schilling, Marcel

AU - Klingmüller, Ursula

PY - 2022/9/20

Y1 - 2022/9/20

N2 - 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 responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations 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-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

AB - 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 responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations 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-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

UR - https://www.scopus.com/pages/publications/85138184864

U2 - 10.1016/j.celrep.2022.111360

DO - 10.1016/j.celrep.2022.111360

M3 - Journal articles

C2 - 36130519

AN - SCOPUS:85138184864

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 111360

ER -

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

Abstract

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