title: Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development.
abstract: Androgen receptor (AR) signaling initiates mouse prostate development by stimulating prostate ductal bud formation and specifying bud patterns. Curiously, however, prostatic bud initiation lags behind the onset of gonadal testosterone synthesis by about three days. This study's objective was to test the hypothesis that DNA methylation controls the timing and scope of prostate ductal development by regulating Ar expression in the urogenital sinus (UGS) from which the prostate derives. We determined that Ar DNA methylation decreases in UGS mesenchyme during prostate bud formation in vivo and that this change correlates with decreased DNA methyltransferase expression in the same cell population during the same time period. To examine the role of DNA methylation in prostate development, fetal UGSs were grown in serum-free medium and 5 alpha dihydrotestosterone (DHT) and the DNA methylation inhibitor 5'-aza-2'-deoxycytidine (5AzadC) were introduced into the medium at specific times. As a measure of prostate development, in situ hybridization was used to visualize and count Nkx3-1 mRNA positive prostatic buds. We determined that inhibiting DNA methylation when prostatic buds are being specified, accelerates the onset of prostatic bud development, increases bud number, and sensitizes the budding response to androgens. Inhibition of DNA methylation also reduces Ar DNA methylation in UGS explants and increases Ar mRNA and protein in UGS mesenchyme and epithelium. Together, these results support a novel mechanism whereby Ar DNA methylation regulates UGS androgen sensitivity to control the rate and number of prostatic buds formed, thereby establishing a developmental checkpoint.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Keil
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Abler
authors.affiliation: Department of Dairy Science, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Laporta
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Helene M
authors.initials: HM
authors.lastname: Altmann
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA; Environmental and Molecular Toxicology, University of Wisconsin, Madison, WI, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
authors.affiliation: Department of Dairy Science, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Hernandez
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: cmvezina@wisc.edu.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Vezina
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives; D001483:Base Sequence; D019175:DNA Methylation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D000077209:Decitabine; D013196:Dihydrotestosterone; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D038081:Organogenesis / Q000502:physiology*; D011467:Prostate / Q000196:embryology*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D011944:Receptors, Androgen; D014157:Transcription Factors; D013196:Dihydrotestosterone; D000077209:Decitabine; D001374:Azacitidine
keywords: Epigenetics; Lower urinary tract; Steroid hormones; UGS