Epigenetic Molecular Mechanisms and Reproductive Transitions

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地打开/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 α）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暴露扰乱了它们的基因表达并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 α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。

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 (ERa) 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 ERa 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.