The classical mode of androgen receptor (AR) action is that it binds to androgen response elements in AR target genes to activate transcription. In this proposal we investigate a new paradigm: that AR also activates transcription by modulating the epigenetic status of certain AR target genes. Our experiments will be conducted in the fetal mouse prostate, an organ that relies on AR activation in prostate mesenchyme for prostatic bud formation. We recently identified a novel androgen-responsive gene in fetal prostate mesenchyme, WNT inhibitory factor 1 (Wif1). We found that WIF1 promotes prostate morphogenesis by enhancing androgen-dependent prostatic bud formation. This proposal's objective is to characterize how androgens activate Wif1 transcription during mouse prostate development.
The Specific Aim will test the hypothesis that AR signaling reduces DNA methylation and increases activating chromatin marks on the Wif1 promoter in fetal mouse prostate mesenchyme. The hypothesis is formulated out of preliminary data from the applicant's laboratory. The rationale for the proposed research is that it is likely to illuminate a novel AR- mediated gene regulatory mechanism that is used to control other androgen-responsive genes. Expected results will be significant because they will reveal DNA methylation as a previously unrecognized regulatory target for androgens, thereby bridging a knowledge gap in understanding how androgens activate gene expression. This research proposal is innovative because it is one of the first to investigate interactions between AR and the developing prostate epigenome.
The proposed research is relevant to human health because it will identify a previously unrecognized mode of androgen action that is likely to control prostate growth and that may be inappropriately activated during prostate disease. The proposed research is therefore relevant to NIH's mission of discovering biological mechanisms responsible for prostate disease.
|Keil, Kimberly P; Abler, Lisa L; Laporta, Jimena et al. (2014) Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development. Dev Biol 396:237-45|
|Keil, Kimberly P; Abler, Lisa L; Mehta, Vatsal et al. (2014) DNA methylation of E-cadherin is a priming mechanism for prostate development. Dev Biol 387:142-53|
|Keil, Kimberly P; Altmann, Helene M; Mehta, Vatsal et al. (2013) Catalog of mRNA expression patterns for DNA methylating and demethylating genes in developing mouse lower urinary tract. Gene Expr Patterns 13:413-24|