The Epigenome: A New Target for Androgen Receptor in Developing Prostate

描述(申请人提供)：雄激素受体(AR)作用的经典模式是它与AR靶基因中的雄激素反应元件结合以激活转录。在这个建议中，我们研究了一种新的范式：AR也通过调节某些AR靶基因的表观遗传状态来激活转录。我们的实验将在胎鼠前列腺中进行，这是一个依赖于前列腺间充质中AR激活的器官，以形成前列腺芽。我们最近在胎儿前列腺间质中发现了一个新的雄激素反应基因，WNT抑制因子1(Wif1)。我们发现WIF1通过促进雄激素依赖的前列腺芽的形成来促进前列腺的形态发生。这项提案的目标是描述雄激素如何在小鼠前列腺发育过程中激活Wif1转录。这一特定的目的将检验这一假设，即AR信号减少了DNA甲基化，并增加了胎鼠前列腺间质中Wif1启动子上的激活染色质标记。这一假设是根据申请人实验室的初步数据提出的。提出这项研究的基本原理是，它可能阐明一种新的AR介导的基因调控机制，用于控制其他雄激素反应基因。预期的结果将是重要的，因为它们将揭示DNA甲基化是以前未被认识到的雄激素调控靶点，从而弥合了在理解雄激素如何激活基因表达方面的知识鸿沟。这项研究方案具有创新性，因为它是第一个研究AR与发育中的前列腺表基因组之间的相互作用的研究方案之一。

DESCRIPTION (provided by applicant): 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.