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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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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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