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.

Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain

“…Because PCBs affected expression of Ar and Oprm1 in the POA and Oprm1 in the PFC of male rats, and the expression of these genes are modulated by DNA methylation (Vucetic et al 2011, Nielsen et al 2009, Hao et al 2011, Keil et al 2014), epigenetic analyses were performed on these targets. We decided to conduct work in both sexes as the Ar is on the X-chromosome and should have much higher methylation in females than males (Walker et al, 2014).…”

“…These effects were distinct from those observed in a similar study, in which prenatal PCBs increased methylation at one different site in males and not females (Walker et al, 2014). DNA methylation of CpG sites is typically thought to reduce accessibility to transcriptional factors and ultimately decrease mRNA expressed (Razin, 1998), and this classic inverse relationship appears to true for Ar in vivo and in reproductive tissues (Jarrard et al, 1998; Keil et al, 2014; J. Tian et al, 2012).…”

Histone acetylation regulates prostate ductal morphogenesis through a bone morphogenetic protein–dependent mechanism

“…Epigenetic modifications are likely to serve an important regulatory mechanism in prostate development. For example, we recently showed that DNA methylation determines Ar and E‐cadherin abundance during the onset and progression of prostatic bud formation (Keil et al, ). Other epigenetic modifications, such as histone acetylation/deacetylation, are also powerful regulators of gene expression but their roles in prostate development have not been examined.…”

5-Aza-2’-deoxycytidine in the medial prefrontal cortex regulates alcohol-related behavior and Ntf3-TrkC expression in rats

“…DNA methylation can maintain long-term stability of related phenotypes by regulating the permanent silencing of specific genes [5, 6]. While several studies support a role of DNA methylation in regulation of alcohol-related behavior [7–9], but much less is known about the exact mechanism.…”