Roles of Estrogen Receptor-α and the Coactivator MED1 During Human Endometrial Decidualization

Abstract

The steroid hormones 17β-estradiol and progesterone are critical regulators of endometrial stromal cell differentiation, known as decidualization, which is a prerequisite for successful establishment of pregnancy. The present study using primary human endometrial stromal cells (HESCs) addressed the role of estrogen receptor-α (ESR1) in decidualization. Knockdown of ESR1 transcripts by RNA interference led to a marked reduction in decidualization of HESCs. Gene expression profiling at an early stage of decidualization indicated that ESR1 negatively regulates several cell cycle regulatory factors, thereby suppressing the proliferation of HESCs as these cells enter the differentiation program. ESR1 also controls the expression of WNT4, FOXO1, and progesterone receptor (PGR), well-known mediators of decidualization. Whereas ESR1 knockdown strongly inhibited the expression of FOXO1 and WNT4 transcripts within 24 hours of the initiation of decidualization, PGR expression remained unaffected at this early time point. Our study also revealed a major role of cAMP signaling in influencing the function of ESR1 during decidualization. Using a proteomic approach, we discovered that the cAMP-dependent protein kinase A (PKA) phosphorylates Mediator 1 (MED1), a subunit of the mediator coactivator complex, during HESC differentiation. Using immunoprecipitation, we demonstrated that PKA-phosphorylated MED1 interacts with ESR1. The PKA-dependent phosphorylation of MED1 was also correlated with its enhanced recruitment to estrogen-responsive elements in the WNT4 gene. Knockdown of MED1 transcripts impaired the expression of ESR1-induced WNT4 and FOXO1 transcripts and blocked decidualization. Based on these findings, we conclude that modulation of ESR1-MED1 interactions by cAMP signaling plays a critical role in human decidualization.

Juxtacrine Activity of Estrogen Receptor α in Uterine Stromal Cells is Necessary for Estrogen-Induced Epithelial Cell Proliferation

“…However, after artificial stimulation, uteri with stromal ESR1 deletion in the anti-mesometrium showed impaired decidual responses as measured by uterine weight increase and cell proliferation. These results confirm recent findings showing ESR1 is required for normal decidualization of cultured human stromal cells 45 .…”

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

“…2 , lower panel). Out of the eleven candidate target genes regulated by rs117245733, the FOXO1 gene is notable, as its expression in primary human endometrial stromal cells is regulated by ESR1 42 and it is a direct protein–protein interaction partner of ESR1 in breast cancer cells 43 . The secondary signal at 13q14.11, rs7986407, also targets FOXO1 (Supplementary Fig.…”

Bisphenol A‐induced mechanistic impairment of decidualization

“…During decidualization in humans, ER is downregulated in the glandular epithelia and stroma of the stratum functionalis but upregulated in the glandular epithelia and stroma of the stratum basalis. (Kaya Okur, Das, Taylor, Bagchi, & Bagchi, 2016). Expressions of both PRA and PRB are reduced in the glandular epithelia, with little or no decrease in PRA expression in the stroma.…”

“…Levels of PRB fluctuate similarly to the PRB levels in the glandular epithelia (Mote, Balleine, McGowan, & Clarke, 1999). Gene expression profiling of ESCs, during early stages of decidualization, revealed that ERα negatively regulates several cell cycle regulatory factors, thereby suppressing the proliferation of ESCs as these cells differentiate into DCs (Kaya Okur et al, 2016).…”