Reversing the Effects of Developmental Reprogramming

描述（由申请人提供）：在发育的关键窗口期的环境暴露可以永久性地重编程正常的生理反应，通过称为“发育重编程”的表观遗传过程促进成人疾病的发展。我们已经证明，异种雌激素，包括大豆植物雌激素染料木素（GEN），在发育中的子宫中诱导非基因组快速雌激素受体（ER）信号，磷酸化组蛋白甲基转移酶EZH2并抑制这种表观遗传调节剂在H3K27处染色质甲基化的能力。这种表观遗传重编程导致成年子宫中雌激素调节基因对雌性激素雌激素的反应性增加，促进这些激素依赖性肿瘤在遗传易感大鼠中的发展。因此，非基因组（或更恰当的“前基因组”）信号的激活在组织发育过程中提供了异雌激素暴露与细胞表观遗传机制之间的直接联系。重要的是，我们最近也在这些大鼠中记录了肿瘤在肥胖的情况下发展，这是女性平滑肌瘤的已知危险因素。在本R21应用中，我们将验证以下假设，即在其他环境中显示的降低癌症风险的干预措施，以及可以逆转肥胖表型的干预措施，将改善异雌激素暴露对平滑肌瘤发病率的影响（Specific Aim 1），有效的干预措施是通过逆转发育重编程诱导的组蛋白甲基化的表观遗传改变来实现的（Specific Aim 2）。这一应用具有重要意义，因为它关注了两个相关的环境因素，肥胖和大豆植物雌激素GEN，以及一种对女性健康有重大不利影响的疾病（子宫平滑肌瘤）。这一应用具有创新性，因为它首次尝试确定可以预防或扭转生命早期接触异雌激素对健康的不利影响的干预措施。在探索性项目中获得的数据将为研究奠定基础，以确定饮食、生活方式和/或药物干预调节表观基因组以降低疾病风险的机制，并在未来确定这些干预措施可以有效降低风险的关键生命周期窗口，为将这些发现转化为人类奠定基础。

DESCRIPTION (provided by applicant): Environmental exposures during critical windows of development can permanently reprogram normal physiological responses, promoting the development of adult disease via an epigenetic process termed "developmental reprogramming". We have demonstrated that xenoestrogens, including the soy phytoestrogen genistein (GEN), induce non-genomic rapid estrogen receptor (ER) signaling in the developing uterus, phosphorylating the histone methyltransferase EZH2 and inhibiting the ability of this epigenetic regulator to methylate chromatin at H3K27. This epigenetic reprogramming results in increased responsiveness of estrogen-regulated genes to the female hormone estrogen in the adult uterus, promoting development of these hormone-dependent tumors in genetically susceptible rats. Thus, activation of non- genomic (or more appropriately "pre-genomic") signaling provides a direct link between xenoestrogen exposure and the cell's epigenetic machinery during tissue development. Importantly, we have also recently documented in these rats that tumors develop in the setting of obesity, a known risk factor for leiomyoma in women. In this R21 application, we will test the hypothesis that interventions that have been shown in other settings to decrease cancer risk, and which can reverse the obesity phenotype, will ameliorate the impact of xenoestrogen exposure on leiomyoma incidence (Specific Aim 1) and that effective interventions do so by reversing epigenetic alterations in histone methylation induced by developmental reprogramming (Specific Aim 2). This application is Significant, as it focuses on two relevant environmental factors, obesity and the soy phytoestrogen GEN, and a disease (uterine leiomyoma) that has a significant adverse effect on women's health. The application is Innovative, as it represents the first attempts to identify interventions that can prevent or reverse the adverse health effects of early life exposures to xenoestrogens. Data obtained in the exploratory project will lay the ground work for studies to identify mechanisms by which dietary, life-style and/or pharmacologic interventions modulate the epigenome to reduce risk of disease, and in the future, identify critical life-cycle windows in which these interventions can be administered to effectively reduce risk, setting the stage for translating these findings to human populations.