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A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism.

ABSTRACT: Differentiation (decidualization) of endometrial stromal cells (ESC) is an essential prerequisite for successful implantation and establishment of pregnancy.The aim was to determine whether the orphan nuclear receptor estrogen-related receptor ? (ERR?, NR3B1), and its target genes, medium chain specific acyl-CoA dehydrogenase (MCAD, ACADM), pyruvate dehydrogenase kinase 4 (PDK4), and phosphoenolpyruvate carboxykinase 2 (PEPCK, PCK2), play a role in the decidualization process.We conducted the study at a University Research Institute.Endometrial tissues were collected from women with regular menstrual cycles; tissues were used for recovery of primary ESC or RNA extraction or were fixed for immunohistochemistry. Primary ESC were decidualized in vitro; some cells were treated with XCT790 (ERR? inverse agonist).Decidualization of ESC in vitro was associated with a significant increase in expression of transcripts encoding ERR? and its coactivator peroxisome proliferator-activated receptor ? coactivator-1 ?. Expression of ERR? target genes was altered with increased expression of MCAD and PDK4 and reduced expression of PEPCK. Incubation of decidualized ESC with XCT790 reduced expression of ERR? and markers of decidualization such as IGFBP-1.Increased expression of ERR? may play a role in altering the bioenergetics of decidualized ESC in preparation for implantation of the embryo and successful establishment of early pregnancy.

SUBMITTER: Bombail V

PROVIDER: S-EPMC3050102 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism.

Bombail Vincent V Gibson Douglas A DA Collins Frances F MacPherson Sheila S Critchley Hilary O D HO Saunders Philippa T K PT

The Journal of clinical endocrinology and metabolism 20100728 10

<h4>Context</h4>Differentiation (decidualization) of endometrial stromal cells (ESC) is an essential prerequisite for successful implantation and establishment of pregnancy.<h4>Objective</h4>The aim was to determine whether the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1), and its target genes, medium chain specific acyl-CoA dehydrogenase (MCAD, ACADM), pyruvate dehydrogenase kinase 4 (PDK4), and phosphoenolpyruvate carboxykinase 2 (PEPCK, PCK2), play a role in the deciduali ...[more]

PMID: 20668045

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Project description:Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal cellular compartments of the human endometrium during the proliferative and secretory phase of the menstrual cycle as well as in cultured HESCs. We also found that SRC-3 depletion in cultured HESCs results in a significant attenuation in the induction of a wide-range of established biomarkers of decidualization, despite exposure of these cells to a deciduogenic stimulus and normal progesterone receptor expression. These molecular findings are supported at the cellular level by the inability of HESCs to morphologically transform from a stromal fibroblastoid cell to an epithelioid decidual cell when endogenous SRC-3 levels are markedly reduced. To identify genes, signaling pathways and networks that are controlled by SRC-3 and potentially important for hormone-dependent decidualization, we performed RNA-sequencing on HESCs in which SRC-3 levels were significantly reduced at the time of administering the deciduogenic stimulus. Comparing HESC controls with HESCs deficient in SRC-3, gene enrichment analysis of the differentially expressed gene set revealed an overrepresentation of genes involved in chromatin remodeling, cell proliferation/motility, and programmed cell death. These predictive bioanalytic results were confirmed by the demonstration that SRC-3 is required for the expansion, migratory and invasive activities of the HESC population, cellular properties that are required in vivo in the formation or functioning of the decidua. Collectively, our results support SRC-3 as an important coregulator in HESC decidualization. Since perturbation of normal homeostatic levels of SRC-3 is linked with common gynecological disorders diagnosed in reproductive age women, this endometrial coregulator-along with its new molecular targets described here-may open novel clinical avenues in the diagnosis and/or treatment of a non-receptive endometrium, particularly in patients presenting non-aneuploid early pregnancy loss.

Dataset Information

A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism.

Publications

A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism.

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