title: 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.
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Ellane R
authors: ER
authors: Cleys
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Jennifer L
authors: JL
authors: Halleran
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Vanessa A
authors: VA
authors: Enriquez
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Juliano C
authors: JC
authors: da Silveira
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Rachel C
authors: RC
authors: West
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Quinton A
authors: QA
authors: Winger
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Russell V
authors: RV
authors: Anthony
authors: 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.
authors: Jason E
authors: JE
authors: Bruemmer
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Colin M
authors: CM
authors: Clay
authors: Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Gerrit J
authors: GJ
authors: Bouma
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010920:Placenta / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D020543:Proteome; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D043343:Testosterone Propionate / Q000494:pharmacology; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000728:Androgens; D020543:Proteome; D011944:Receptors, Androgen; D042461:Vascular Endothelial Growth Factor A; D056466:Histone Demethylases; D043343:Testosterone Propionate