Cleys Ellane R, Halleran Jennifer L, Enriquez Vanessa A, da Silveira Juliano C, West Rachel C, Winger Quinton A, Anthony Russell V, Bruemmer Jason E, Clay Colin M, Bouma Gerrit J
Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America; Department of Animal Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
PLoS One. 2015 Feb 12;10(2):e0117472. doi: 10.1371/journal.pone.0117472. eCollection 2015.
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.
性类固醇激素调节许多组织中的发育编程，包括产前发育期间的基因表达编程。虽然已知雌二醇调节胎盘形成，但尽管睾酮在孕期母血循环以及胎盘诱导的妊娠疾病中升高，但关于睾酮和雄激素信号在胎盘发育中的作用却知之甚少。我们研究了睾酮在胎盘基因表达中的作用，并聚焦于雄激素受体（AR）。产前雄激素化降低了妊娠90天胎盘小叶中的整体DNA甲基化，并增加了AR以及参与表观遗传调控、血管生成和生长的基因的胎盘表达。由于在人类癌症中AR与组蛋白赖氨酸去甲基化酶（KDMs）结合以调节AR靶基因，我们还研究了绵羊胎盘是否存在相同机制。在绵羊胎盘小叶中，AR与KDM1A和KDM4D共免疫沉淀，并且AR-KDM1A复合物被募集到VEGFA启动子区域中雄激素反应元件（ARE）的半位点。雄激素化的母羊的子叶VEGFA也增加。最后，在人类孕早期胎盘样本中，KDM1A和KDM4D免疫定位到合体滋养层，绒毛基质中也存在核KDM1A和KDM4D免疫染色。总之，胎盘雄激素信号可能通过AR-KDM复合物募集到AREs来调节胎盘VEGFA表达。AR和KDMs也存在于孕早期人类胎盘中。雄激素似乎是滋养层分化和胎盘发育的重要调节因子，异常的雄激素信号可能导致胎盘疾病的发生。
