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Estrogen Receptor (ER) Mediates Stimulatory Effects of Estrogen on Aromatase (CYP19) Gene Expression in Human Placenta

Departments of Biochemistry and Obstetrics and Gynecology (P.K., C.R.M.), North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; and Department of Medicine (A.K.), University of Texas Health Science Center at San Antonio, Geriatric Research, Education and Clinical Center, Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Carole R. Mendelson, Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038. E-mail: carole.mendelson{at}utsouthwestern.edu.

A 246-bp region upstream of placenta-specific exon I.1 of the human aromatase (hCYP19) gene mediates placenta-specific, developmental, and O₂ regulation of expression. In this study, trophoblast differentiation and associated induction of CYP19 expression were prevented when cytotrophoblasts were cultured in phenol red-free medium containing charcoal-stripped serum or with the estrogen receptor (ER) antagonist, ICI 182,780, suggesting a stimulatory role of estrogen/ER. ER protein was expressed in human trophoblasts and increased during syncytiotrophoblast differentiation, whereas ERβ was undetectable. Mutational analysis revealed that an estrogen response element-like sequence (ERE-LS) at –208 bp is required for inductive effects of estradiol/ER on hCYP19I.1 promoter activity in transfected COS-7 cells. Increased binding of syncytiotrophoblast compared with cytotrophoblast nuclear proteins to the ERE-LS was observed in vitro; however, ER antibodies failed to supershift the complex and in vitro-transcribed/translated ER did not bind. Nonetheless, chromatin immunoprecipitation assays in cultured trophoblasts revealed recruitment of endogenous ER to the –255- to –155-bp region containing the ERE-LS before induction of hCYP19 expression; this was inhibited by ICI 182,780. Chromatin immunoprecipitation also revealed increased acetylated histone H3(K9/14) and decreased methylated histone H3(K9) associated with this region during trophoblast differentiation. These modifications were prevented when trophoblasts were incubated with ICI 182,780, suggesting that ER recruitment to the –255- to –155-bp region promotes histone modifications leading to increased hCYP19 transcription. Thus, during trophoblast differentiation, estrogen/ER exerts a positive feedback role, which promotes permissive histone modifications that are associated with induction of hCYP19 gene transcription.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  Fulvestrant