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Cooperative control via lymphoid enhancer factor 1/T cell factor 3 and estrogen receptor-alpha for uterine gene

Sanhita Ray1, Fuhua Xu, Haibin Wang

  • 1Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2678, USA.

Molecular Endocrinology (Baltimore, Md.)
|January 19, 2008
PubMed

Insights

Estrogen (E2) regulates uterine genes through both classical estrogen receptor (ER) and non-classical beta-catenin pathways. This study reveals ER-independent Lef-1/Tcf-3 signaling cooperates with ERalpha at chromatin to control estrogen-responsive gene expression.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Reproductive Biology

Background:

  • Estrogen (E2) exerts pleiotropic effects via estrogen receptors (ERs) and also through ER-independent pathways.
  • The molecular interplay between ER-dependent and ER-independent signaling in mediating E2's effects on gene regulation, particularly in the uterus, remains largely unexplored.

Purpose of the Study:

  • To investigate the molecular relationship between ER-independent Wnt/beta-catenin signaling and ERalpha in mediating estrogen's regulation of gene expression in the mouse uterus.
  • To elucidate the temporal dynamics and functional significance of the interaction between lymphoid enhancer factor 1 (Lef-1)/T cell factor 3 (Tcf-3) and ERalpha.

Main Methods:

  • Temporal analysis of Lef-1 and Tcf-3 expression in mouse uterus following 17beta-estradiol (E2) treatment.
  • Dual immunofluorescence to confirm colocalization of Lef-1/Tcf-3 and ERalpha.
  • Chromatin immunoprecipitation followed by PCR (ChIP-PCR) to assess binding of ERalpha and Lef-1/Tcf-3 complex to target gene promoters.
  • Selective perturbation of Lef-1/Tcf-3 and ERalpha signaling pathways.

Main Results:

  • 17beta-estradiol (E2) up-regulates Lef-1 and Tcf-3 in an ER-independent manner in the uterus, with distinct temporal induction patterns.
  • Activated Lef-1/Tcf-3 interacts with ERalpha in a time-dependent manner and colocalizes in uterine epithelial cells.
  • ERalpha and the Lef-1/Tcf-3 complex bind to specific DNA regions of estrogen-responsive gene promoters.
  • Cooperative interaction between Lef-1/Tcf-3 and ERalpha at the chromatin level is crucial for regulating estrogen-responsive genes.

Conclusions:

  • Estrogen-dependent uterine gene regulation involves the integration of non-classical beta-catenin/Lef-1/Tcf-3 signaling with classical ERalpha signaling.
  • This cooperative interaction at the chromatin level represents a novel mechanism for precise control of estrogen-responsive gene expression in the uterus.

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