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Transcriptional control and signal transduction, cell cycle

Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1

Leukemia volume 31, pages 945–956 (2017)Cite this article

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Abstract

Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte (MK) differentiation and its deficiency will lead to megakaryoblastic leukemia. Here we show that estrogen can dose-dependently promote MK polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant upregulation of GATA1. Chromatin immunoprecipitation and a dual luciferase assay demonstrate that ERβ can directly bind the promoter region of GATA1 and activate its transcription. Steroid receptor coactivator 3 (SRC3) is involved in ERβ-mediated GATA1 transcription. The deficiency of ERβ or SRC3, similar to the inhibition of GATA1, leads to the impediment of estrogen-induced MK polyploidization and platelet production. Further investigations reveal that signal transducer and activator of transcription 1 signaling pathway downstream of GATA1 has a crucial role in estrogen-induced MK polyploidization, and ERβ-mediated GATA1 upregulation subsequently enhances nuclear factor erythroid-derived 2 expression, thereby promoting proplatelet formation and platelet release. Our study provides a deep insight into the molecular mechanisms of estrogen signaling in regulating thrombopoiesis and the pathogenesis of ER deficiency-related leukemia.

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References

  1. Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 2014; 505: 555–558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sanchez-Aguilera A, Arranz L, Martin-Perez D, Garcia-Garcia A, Stavropoulou V, Kubovcakova L et al. Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis. Cell Stem Cell 2014; 15: 791–804.

    Article  CAS  PubMed  Google Scholar 

  3. Fish EN . The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 2008; 8: 737–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lopes BA, Emerenciano M, Goncalves BA, Vieira TM, Rossini A, Pombo-de-Oliveira MS . Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 are associated with early age acute leukemia. PLoS One 2015; 10: e0127308.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Howlader N, Noone A, Krapcho M, Neyman N, Aminou R, Waldron W et al. SEER Cancer Statistics Review, 1975–2008. National Cancer Institute: Bethesda, MD, USA, 2011, p 19.

    Google Scholar 

  6. Catovsky D, Fooks J, Richards S . Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival. A report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br J Haematol 1989; 72: 141–149.

    Article  CAS  PubMed  Google Scholar 

  7. Chen S, Su Y, Wang J . ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation. Cell Death Dis 2013; 4: e722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pohle FJ . The blood platelet count in relation to the menstrual cycle in normal women. Am J Med Sci 1939; 197: 40–46.

    Article  Google Scholar 

  9. Bord S, Vedi S, Beavan SR, Horner A, Compston JE . Megakaryocyte population in human bone marrow increases with estrogen treatment: a role in bone remodeling? Bone 2000; 27: 397–401.

    Article  CAS  PubMed  Google Scholar 

  10. Zierk J, Arzideh F, Rechenauer T, Haeckel R, Rascher W, Metzler M et al. Age- and sex-specific dynamics in 22 hematologic and biochemical analytes from birth to adolescence. Clin Chem 2015; 61: 964–973.

    Article  CAS  PubMed  Google Scholar 

  11. Bord S, Frith E, Ireland DC, Scott MA, Craig JI, Compston JE . Estrogen stimulates differentiation of megakaryocytes and modulates their expression of estrogen receptors alpha and beta. J Cell Biochem 2004; 92: 249–257.

    Article  CAS  PubMed  Google Scholar 

  12. Fox SW, Chambers TJ . The effect of oestrogen on megakaryocyte differentiation and platelet counts in vivo. Int J Cardiol 2006; 109: 359–366.

    Article  PubMed  Google Scholar 

  13. Machlus KR, Italiano JE Jr. . The incredible journey: From megakaryocyte development to platelet formation. J Cell Biol 2013; 201: 785–796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thon JN, Italiano JE . Platelet formation. Semin Hematol 2010; 47: 220–226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cramer EM, Norol F, Guichard J, Breton-Gorius J, Vainchenker W, Masse JM et al. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 1997; 89: 2336–2346.

    CAS  PubMed  Google Scholar 

  16. Tijssen MR, Ghevaert C . Transcription factors in late megakaryopoiesis and related platelet disorders. J Thromb Haemost 2013; 11: 593–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vyas P, Ault K, Jackson CW, Orkin SH, Shivdasani RA . Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 1999; 93: 2867–2875.

    CAS  PubMed  Google Scholar 

  18. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32: 148–152.

    Article  CAS  PubMed  Google Scholar 

  19. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87: 905–931.

    Article  CAS  PubMed  Google Scholar 

  20. O'Lone R, Frith MC, Karlsson EK, Hansen U . Genomic targets of nuclear estrogen receptors. Mol Endocrinol 2004; 18: 1859–1875.

    Article  CAS  PubMed  Google Scholar 

  21. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997; 90: 569–580.

    Article  CAS  PubMed  Google Scholar 

  22. Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M . Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 2000; 103: 843–852.

    Article  CAS  PubMed  Google Scholar 

  23. Khetawat G, Faraday N, Nealen ML, Vijayan KV, Bolton E, Noga SJ et al. Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression. Blood 2000; 95: 2289–2296.

    CAS  PubMed  Google Scholar 

  24. Shim GJ, Wang L, Andersson S, Nagy N, Kis LL, Zhang Q et al. Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. Proc Natl Acad Sci USA 2003; 100: 6694–6699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O'Malley BW . The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci 2000; 97: 6379–6384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N . Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol 2005; 239: 27–36.

    Article  CAS  PubMed  Google Scholar 

  27. Xu Y, Wang S, Shen M, Zhang Z, Chen S, Chen F et al. hGH promotes megakaryocyte differentiation and exerts a complementary effect with c-Mpl ligands on thrombopoiesis. Blood 2014; 123: 2250–2260.

    Article  CAS  PubMed  Google Scholar 

  28. Coste A, Antal MC, Chan S, Kastner P, Mark M, O'Malley BW et al. Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J 2006; 25: 2453–2464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang Z, Richmond TD, Muntean AG, Barber DL, Weiss MJ, Crispino JD . STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. J Clin Invest 2007; 117: 3890–3899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ . Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci USA 1995; 92: 5292–5296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kirito K, Osawa M, Morita H, Shimizu R, Yamamoto M, Oda A et al. A functional role of Stat3 in in vivo megakaryopoiesis. Blood 2002; 99: 3220–3227.

    Article  CAS  PubMed  Google Scholar 

  32. Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995; 81: 695–704.

    Article  CAS  PubMed  Google Scholar 

  33. Pawlikowska P, Fouchet P, Vainchenker W, Rosselli F, Naim V . Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice. Blood 2014; 124: 3613–3623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Blobel GA, Sieff CA, Orkin SH . Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor. Mol Cell Biol 1995; 15: 3147–3153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cui J, Shen Y, Li R . Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 2013; 19: 197–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McDonnell DP, Norris JD . Connections and regulation of the human estrogen receptor. Science 2002; 296: 1642–1644.

    Article  CAS  PubMed  Google Scholar 

  37. Jin J, Wang Y, Wang J, Xu Y, Chen S, Wang J et al. Impaired hematopoiesis and delayed thrombopoietic recovery following sublethal irradiation in SRC-3 knockout mice. Mol Med Rep 2014; 9: 1629–1633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jin J, Wang Y, Wang J, Xu Y, Chen S, Wang J et al. Increased radiosensitivity and radiation-induced apoptosis in SRC-3 knockout mice. J Radiat Res 2014; 55: 443–450.

    Article  CAS  PubMed  Google Scholar 

  39. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ et al. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 1997; 90: 109–119.

    Article  CAS  PubMed  Google Scholar 

  40. Blobel GA, Nakajima T, Eckner R, Montminy M, Orkin SH . CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. Proc Natl Acad Sci USA 1998; 95: 2061–2066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell 1994; 77: 1117–1124.

    Article  CAS  PubMed  Google Scholar 

  42. Avraham H, Vannier E, Cowley S, Jiang SX, Chi S, Dinarello CA et al. Effects of the stem cell factor, c-kit ligand, on human megakaryocytic cells. Blood 1992; 79: 365–371.

    CAS  PubMed  Google Scholar 

  43. Hodohara K, Fujii N, Yamamoto N, Kaushansky K . Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK). Blood 2000; 95: 769–775.

    CAS  PubMed  Google Scholar 

  44. Bruno E, Cooper RJ, Briddell RA, Hoffman R . Further examination of the effects of recombinant cytokines on the proliferation of human megakaryocyte progenitor cells. Blood 1991; 77: 2339–2346.

    CAS  PubMed  Google Scholar 

  45. Chen S, Du C, Shen M, Zhao G, Xu Y, Yang K et al. Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation. Blood 2016; 127: 1024–1035.

    Article  CAS  PubMed  Google Scholar 

  46. Drachman JG, Sabath DF, Fox NE, Kaushansky K . Thrombopoietin signal transduction in purified murine megakaryocytes. Blood 1997; 89: 483–492.

    CAS  PubMed  Google Scholar 

  47. Liu RY, Fan C, Garcia R, Jove R, Zuckerman KS . Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. Blood 1999; 93: 2369–2379.

    CAS  PubMed  Google Scholar 

  48. Takayama M, Fujita R, Suzuki M, Okuyama R, Aiba S, Motohashi H et al. Genetic analysis of hierarchical regulation for Gata1 and NF-E2 p45 gene expression in megakaryopoiesis. Mol Cell Biol 2010; 30: 2668–2680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nagata Y, Yoshikawa J, Hashimoto A, Yamamoto M, Payne AH, Todokoro K . Proplatelet formation of megakaryocytes is triggered by autocrine-synthesized estradiol. Genes Dev 2003; 17: 2864–2869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Patmasiriwat P, Fraizer G, Kantarjian H, Saunders GF . WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia. Leukemia 1999; 13: 891–900.

    Article  CAS  PubMed  Google Scholar 

  51. Jilka RL, Passeri G, Girasole G, Cooper S, Abrams J, Broxmeyer H et al. Estrogen loss upregulates hematopoiesis in the mouse: a mediating role of IL-6. Exp Hematol 1995; 23: 500–506.

    CAS  PubMed  Google Scholar 

  52. Issa JP, Baylin SB, Herman JG . DNA methylation changes in hematologic malignancies: biologic and clinical implications. Leukemia 1997; 11 (Suppl 1): S7–S11.

    PubMed  Google Scholar 

  53. Yakimchuk K, Iravani M, Hasni MS, Rhonnstad P, Nilsson S, Jondal M et al. Effect of ligand-activated estrogen receptor beta on lymphoma growth in vitro and in vivo. Leukemia 2011; 25: 1103–1110.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Xiaolan Fu and Dr Yang Liu for technical support for FACS. We thank Wei Jiang for technical help and assistance with animal procedures. This work was supported by grants from the National Natural Science Fund of China (Nos. 81500087, 81573084, 81502755), the Funds of Key Laboratory of Trauma, Burn and Combined Injury (Nos. SKLZZ201504, SKLZZ201115), the grant from PLA (No. AWS16J014) and the Program for Scientific and Technological Innovation Leader of Chongqing (CSTCKJCXLJRC06).

Author contributions

CD performed experiments, analyzed data and wrote the paper. YX and KY performed experiments, analyzed data and participated in manuscript preparation. SC, XW, MS, SW and MC contributed to animal experiments and data analysis. CW, FC, DZ and FL contributed to the in vitro experiments and image scoring. TW, FW, JZ, GA, TC and YS contributed to the initial experimental design and discussed the manuscript. JW conceived and supervised the study, analyzed the data and wrote and revised the manuscript.

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  1. C Du, Y Xu and K Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China

    C Du, Y Xu, K Yang, S Chen, X Wang, S Wang, C Wang, M Shen, F Chen, M Chen, D Zeng, F Li, T Wang, F Wang, G Ai, T Cheng, Y Su & J Wang

  2. Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    K Yang & J Zhao

  3. Department of Hematology, Daping Hospital, Third Military Medical University, Chongqing, China

    D Zeng

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Correspondence to J Wang.

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Du, C., Xu, Y., Yang, K. et al. Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1. Leukemia 31, 945–956 (2017). https://doi.org/10.1038/leu.2016.285

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