Epigenetic Molecular Mechanisms and Reproductive Transitions

描述（由申请人提供）：生物体获得和维持生殖能力的能力涉及一套下丘脑基因的复杂协调，这些基因必须与生命阶段和环境协调开启/关闭。调节生殖神经内分泌基因表达的因素包括循环性类固醇激素，包括雌二醇。虽然需要性激素以年龄和性别依赖的方式调节生殖生命的转变，但其潜在机制尚未得到很好的理解。这项建议的重点是阐明表观遗传的分子机制，生物体的激素环境调节其下丘脑基因的表达，以确保适当的生殖生理与生命阶段的协调。重点将是雌激素受体α（ER 1）和kisspeptin，选择这些下丘脑基因是因为它们以性二态的方式表达，它们在整个生命周期中经历了强烈的变化，并且因为在早期生命发育过程中外源性雌激素的暴露扰乱了它们的基因表达，破坏了生殖发育和衰老。目的1检测DNA甲基化的表观遗传修饰是否影响下丘脑区域ER 1和kisspeptin基因表达的编程。目的2将测试的假设，即组蛋白乙酰化的表观遗传事件是重要的激活和维持这些基因的表达在成年期，并在生殖衰老的过程中。实验将在雄性和雌性大鼠中进行，按性别和年龄进行比较。一部分动物将暴露于产前雌二醇，这会破坏生殖过程并加速生殖衰老。总的来说，这些研究将提供新的表观遗传分子数据的组织和维护所需的关键下丘脑基因的适当的生殖功能，并进一步阐明基因表达和激素环境之间的联系。 公共卫生相关性：拟议中的大鼠实验与人类健康高度相关，因为生殖的激素和生理学是高度保守的。这些研究对于理解作为更年期（女性）/“男性更年期”（男性）模型的生殖功能丧失特别重要。虽然它们不是疾病，但这些生活转变与心血管疾病、乳腺癌、前列腺癌和子宫癌、代谢紊乱和骨质疏松症的风险相当高有关，所有这些都是激素依赖性的。此外，这些生活变化与中枢神经系统问题有关，包括潮热，睡眠剥夺，抑郁和焦虑。因此，更好地了解调节这些事件的神经分子机制可能有助于促进健康衰老。

DESCRIPTION (provided by applicant): The ability of an organism to attain and maintain reproductive competence involves the intricate coordination of a suite of hypothalamic genes that must be turned on/off in coordination with the life stage and the environment. Among those factors regulating reproductive neuroendocrine gene expression are circulating sex steroid hormones, including estradiol. While sex hormones are required to modulate reproductive life transitions in both an age- and sex-dependent manner, their underlying mechanisms are not well understood. This proposal focuses on elucidating the epigenetic molecular mechanisms by which an organism's hormonal environment modulates its hypothalamic gene expression to ensure the coordination of proper reproductive physiology with life stage. The focus will be the estrogen receptor alpha (ER1) and kisspeptin, chosen because these hypothalamic genes are expressed in a sexually dimorphic manner, they undergo robust changes across the life cycle, and because exogenous estrogen exposure during early life development perturbs their gene expression and disrupts reproductive development and aging. Aim 1 will test whether the epigenetic modification of DNA methylation affects the programming of ER1 and kisspeptin gene expression in hypothalamic regions. Aim 2 will test the hypothesis that the epigenetic event of histone acetylation is important for the activation and maintenance of the expression of these genes in adulthood, and during the process of reproductive senescence. Experiments will be carried out in male and female rats, making comparisons by sex and age. A subset of animals will be exposed to prenatal estradiol, which disrupts reproductive processes and hastens reproductive aging. As a whole, these studies will provide novel epigenetic molecular data on the organization and maintenance of key hypothalamic genes required for proper reproductive function and further illuminates the link between gene expression and the hormonal environment. PUBLIC HEALTH RELEVANCE: The proposed experiments in rats are highly relevant to human health because the hormones and physiology of reproduction are highly conserved. These studies are particularly important for understanding the loss of reproductive function as a model for menopause (women) /"andropause" (men). Although they are not diseases, these life transitions are associated with considerably elevated risk for cardiovascular disease, breast, prostate and uterine cancer, metabolic disorders and osteoporosis, all of which are hormone- dependent. Additionally, these life changes are associated with central nervous system problems including hot flashes, sleep deprivation, depression and anxiety. Therefore, a better understanding of the neural molecular mechanisms regulating these events could prove beneficial to promoting healthy aging.