Abstract
Two and half million red blood cells (RBC) are generated every second in a healthy adult. The process of RBC production known as erythropoiesis requires a meticulous synchrony between signaling processes and the activity of many transcription factor complexes. FOXO3 is a transcription factor that is responsive to signaling processes and essential for the erythroid proliferation and maturation, RBC formation, and lifespan. Here, we discuss how using an integrated computational and experimental systems biology approach new and unanticipated FOXO3 functions in terminal erythropoiesis were uncovered. These combinatory approaches identified FOXO3 as a key regulator of terminal erythropoiesis. As a result, a new mode of FOXO3 participation in erythroid transcription complex formation has been proposed.
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References
Kerenyi MA, Orkin SH (2010) Networking erythropoiesis. J Exp Med 207:2537–2541
Ferreira R, Ohneda K, Yamamoto M, Philipsen S (2005) GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol 25:1215–1227
Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, Regan M, Weatherall D, Chou DP, Eisele TP, Flaxman SR, Pullan RL, Brooker SJ, Murray CJ (2014) A systematic analysis of global anemia burden from 1990 to 2010. Blood 123:615–624
Goodman SB, Block MH (1967) Increased red blood cell production in chronic myelocytic leukemia. JAMA 200:621–624
Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136
Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97
Bakker WJ, Blazquez-Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Lowenberg B, von Lindern M, van Dijk TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J Cell Biol 164:175–184
Bakker WJ, van Dijk TB, Parren-van Amelsvoort M, Kolbus A, Yamamoto K, Steinlein P, Verhaak RG, Mak TW, Beug H, Lowenberg B, von Lindern M (2007) Differential regulation of Foxo3a target genes in erythropoiesis. Mol Cell Biol 27:3839–3854
Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R (2003) Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 100:6523–6528
Kashii Y, Uchida M, Kirito K, Tanaka M, Nishijima K, Toshima M, Ando T, Koizumi K, Endoh T, Sawada K, Momoi M, Miura Y, Ozawa K, Komatsu N (2000) A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction. Blood 96:941–949
Marinkovic D, Zhang X, Yalcin S, Luciano JP, Brugnara C, Huber T, Ghaffari S (2007) Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 117:2133–2144
Liang R, Camprecios G, Kou Y, McGrath K, Nowak R, Catherman S, Bigarella CL, Rimmele P, Zhang X, Gnanapragasam MN, Bieker JJ, Papatsenko D, Ma'ayan A, Bresnick E, Fowler V, Palis J, Ghaffari S (2015) A systems approach identifies essential FOXO3 functions at key steps of terminal erythropoiesis. PLoS Genet 11:e1005526
Franco SS, De Falco L, Ghaffari S, Brugnara C, Sinclair DA, Matte A, Iolascon A, Mohandas N, Bertoldi M, An X, Siciliano A, Rimmele P, Cappellini MD, Michan S, Zoratti E, Anne J, De Franceschi L (2014) Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice. Haematologica 99:267–275
Yu D, dos Santos CO, Zhao G, Jiang J, Amigo JD, Khandros E, Dore LC, Yao Y, D'Souza J, Zhang Z, Ghaffari S, Choi J, Friend S, Tong W, Orange JS, Paw BH, Weiss MJ (2010) miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta. Genes Dev 24:1620–1633
McIver SC, Kang YA, DeVilbiss AW, O’Driscoll CA, Ouellette JN, Pope NJ, Camprecios G, Chang CJ, Yang D, Bouhassira EE, Ghaffari S, Bresnick EH (2014) The exosome complex establishes a barricade to erythroid maturation. Blood 124:2285–2297
Zhang X, Camprecios G, Rimmele P, Liang R, Yalcin S, Mungamuri SK, Barminko J, D’Escamard V, Baron MH, Brugnara C, Papatsenko D, Rivella S, Ghaffari S (2014) FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis. Am J Hematol 89:954–963
Lachmann A, Xu H, Krishnan J, Berger SI, Mazloom AR, Ma’ayan A (2010) ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26:2438–2444
Acknowledgments
The work in the Ghaffari lab is supported by grants from National Institutes of Health (NCI and NHLBI). Raymond Liang is supported by a pre-doctoral fellowship from the American Heart Association.
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Liang, R., Menon, V., Ghaffari, S. (2019). Following Transcriptome to Uncover FOXO Biological Functions. In: Link, W. (eds) FOXO Transcription Factors. Methods in Molecular Biology, vol 1890. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-8900-3_18
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DOI: https://doi.org/10.1007/978-1-4939-8900-3_18
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