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

Leukemia. 2017 Apr;31(4):945-956. doi: 10.1038/leu.2016.285. Epub 2016 Oct 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Dose-Response Relationship, Drug
  • Estrogen Receptor beta / metabolism*
  • Estrogens / pharmacology*
  • Fetal Blood / cytology
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / metabolism*
  • Gene Expression Regulation
  • Humans
  • Megakaryocytes / drug effects*
  • Megakaryocytes / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivator 3 / metabolism
  • Polyploidy*
  • STAT1 Transcription Factor / metabolism
  • Thrombopoiesis / drug effects
  • Thrombopoiesis / genetics
  • Transcription, Genetic

Substances

  • Estrogen Receptor beta
  • Estrogens
  • GATA1 Transcription Factor
  • STAT1 Transcription Factor
  • Nuclear Receptor Coactivator 3