Advertisement

Following Transcriptome to Uncover FOXO Biological Functions

  • Raymond Liang
  • Vijay Menon
  • Saghi GhaffariEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1890)

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.

Key words

Erythropoiesis Red blood cell (RBC) Enucleation Mitochondria Mitophagy FOXO FOXO3 Transcriptome RNA sequencing 

Notes

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.

References

  1. 1.
    Kerenyi MA, Orkin SH (2010) Networking erythropoiesis. J Exp Med 207:2537–2541CrossRefGoogle Scholar
  2. 2.
    Ferreira R, Ohneda K, Yamamoto M, Philipsen S (2005) GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol 25:1215–1227CrossRefGoogle Scholar
  3. 3.
    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 123:615–624CrossRefGoogle Scholar
  4. 4.
    Goodman SB, Block MH (1967) Increased red blood cell production in chronic myelocytic leukemia. JAMA 200:621–624CrossRefGoogle Scholar
  5. 5.
    Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136CrossRefGoogle Scholar
  6. 6.
    Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97CrossRefGoogle Scholar
  7. 7.
    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 164:175–184CrossRefGoogle Scholar
  8. 8.
    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 27:3839–3854CrossRefGoogle Scholar
  9. 9.
    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 100:6523–6528CrossRefGoogle Scholar
  10. 10.
    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 96:941–949PubMedGoogle Scholar
  11. 11.
    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 117:2133–2144CrossRefGoogle Scholar
  12. 12.
    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:e1005526CrossRefGoogle Scholar
  13. 13.
    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 99:267–275CrossRefGoogle Scholar
  14. 14.
    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 24:1620–1633CrossRefGoogle Scholar
  15. 15.
    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 124:2285–2297CrossRefGoogle Scholar
  16. 16.
    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 89:954–963CrossRefGoogle Scholar
  17. 17.
    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 26:2438–2444CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Raymond Liang
    • 1
    • 2
  • Vijay Menon
    • 1
  • Saghi Ghaffari
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Cell, Developmental and Regenerative BiologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Developmental and Stem Cell Biology Multidisciplinary Training AreaIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Black Family Stem Cell InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations