Binding to estrogen receptor (ER)-α leads to Induction of GATA3 expression

The hormone binding domain (HBD) of the ERα is required not only for binding ligand but also to form stable homodimers of the protein and mediate transcriptional activation by the receptor.  There are two ligand-dependent signaling pathway.  One is “classical” and the other is “tethered” pathway.  A direct genomic interaction occurs between the ER ligand complex and specific sequences of DNA known as estrogen response elements (ERE) (Parker MG. 1993, Goldstein RA. 1993, Sasson S. 1991, Brandt ME. 1997).  Transcriptional activation by ERα is mediated by two distinct activation functions: the constitutively active AF-1 domain, located in the N-terminal domain of the receptor protein, and the ligand-dependent AF-2 domain, located in the C-terminal domain of the receptor protein (Delaunay F. 2000).  This is called “classical” signaling pathway.  In addition to above classical mechanism, ligand-activated ERα interact with other transcription factor complexes and bind to non-EREs by attaching to other transcription factors and not with ERE directly. (Carolyn MK. 2001).  This is also called “tethered” signaling pathway.  The transcription factors GATA3 and STAT6 are essential for the establishment and/or maintenance of these interactions (Spilianakis and Flavell, 2004).  In the tethered pathway, STAT6-ER fusion protein induce GATA-3 mRNA expression.  Furthermore, in mammary gland but not in immune cells, GATA3 and ERα regulate each other and, along with FOXA1, can nucleate a remodeling complex at heterochromatic enhancer regions of ERα target genes, leading to the opening and epigenetic marking of sites for active transcription (Eeckhoute J. 2007, Kong SL. 2011).  Alone, FOXA1 or ERα are not sufficient to fully open the chromatin, supporting a bona fide pioneer activity for GATA3 (Eeckhoute J. 2007, Kong SL. 2011).

The Th1/Th2 shift is one of the most important immunologic changes during the menstrual cycle and gestation.  Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity and higher luteal-phase Th2 cell activity (Tierney KL. 2015).  This is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses (Doria A. 2006).  The effects of ERα signaling on T cells appear to be estrogen-dose dependent, i.e., low doses of estrogen stimulate a Th1 response, but higher doses promote a Th2 response (Priyanka HP. 2013).

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