Androgen Receptor and Histone Lysine Demethylases in Ovine Placenta

Abstract

Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR). Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs) to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE) in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.

Citrullination regulates the expression of insulin-like growth factor-binding protein 1 (IGFBP1) in ovine uterine luminal epithelial cells

“…Functionally, PADs antagonize histone arginine methylation by coactivator associated arginine methyltransferase (CARM1) and protein arginine methyltransferase (PRMT1) (Wang et al 2004). In addition to PADs, multiple isoforms of histone lysine demethylase are expressed in caruncle tissue from gestation day 90 ewes (Cleys et al 2015). Interestingly, both epigenetic enzymes function as demethylases, which may be an important mechanism to regulate gene programs during pregnancy in ewe caruncle tissues.…”

LIN28B regulates androgen receptor in human trophoblast cells through Let‐7c

“…Contrary to mice, human trophoblast cells primarily express LIN28B (Canfield et al, 2018;West et al, 2018), and in this study we explored the possibility that androgen receptor (AR) is a potential target for LIN28B. AR localizes to villous stromal cells, cytotrophoblast, and syncytiotrophoblast in term placenta (Iwamura, Abrahamsson, Benning, Cockett, & di Sant'Agnese, 1994;Horie, Takakura, Imai, Liao, & Mori, 1992), and previous work in our lab suggests AR is involved in regulating placental angiogenesis through its interaction with VEGFA during pregnancy (Cleys et al, 2014). Considering AR is a known regulator of cell proliferation and migration in cancer cells, we recently postulated this also may be true in trophoblast cells during early placental development (McWhorter, Russ, Winger, & Bouma, 2018).…”

Porphyromonas gingivalisand adverse pregnancy outcome

“…One study demonstrated that both Prevotella intermedia and P. gingivalis are able to reduce testosterone to 5-alpha dihydrotestosterone (DHT) and induce DHT synthesis by fibroblasts [22]. More recently, a study investigating the role of androgen regulation during placentation showed that the placenta uses both androgen receptors and histone lysine demethylases to mediate androgen signaling and epigenetic regulation of gene expression during placental development [23]. These authors suggested that abnormal androgen signaling might alter placental development.…”