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

描述（由申请人提供）：雄激素受体（AR）作用的经典模式是与AR靶基因中的雄激素反应元件结合以激活转录。在这个提议中，我们研究了一个新的范例：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，该器官依赖于前列腺间充质中的AR激活以形成前列腺芽。我们最近在胎儿前列腺间质中发现了一种新的雄激素反应基因，WNT抑制因子1（Wif1）。我们发现WIF1通过增强雄激素依赖的前列腺芽形成来促进前列腺形态发生。该提案的目的是描述雄激素如何在小鼠前列腺发育过程中激活Wif1转录。特异性目的将检验以下假设：在胎鼠前列腺间质中，AR信号降低DNA甲基化并增加Wif1启动子上的活化染色质标记。该假设是根据申请人实验室的初步数据制定的。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。预期结果将是重要的，因为它们将揭示DNA甲基化作为以前未被认识到的雄激素调控靶点，从而弥合了理解雄激素如何激活基因表达的知识差距。这项研究提案是创新的，因为它是第一个研究AR与发育中的前列腺表观基因组之间相互作用的研究之一。 公共卫生相关性：这项拟议的研究与人类健康有关，因为它将确定一种以前未被认识到的雄激素作用模式，这种模式可能控制前列腺生长，并且可能在前列腺疾病期间被不适当地激活。因此，拟议的研究与NIH发现前列腺疾病生物机制的使命相关。

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. PUBLIC HEALTH RELEVANCE: 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.