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错综复杂的下丘脑基因的协调，这些基因必须与生命阶段和环境相协调地打开/关闭。在这些调节生殖神经内分泌基因表达的因素中，有循环性类固醇激素，包括雌二醇。虽然性激素需要以年龄和性别相关的方式来调节生殖生活的转变，但其潜在的机制还没有被很好地理解。这项建议侧重于阐明生物激素环境调节其下丘脑基因表达以确保适当的生殖生理与生命阶段协调的表观遗传学分子机制。焦点将是雌激素受体α(ERA)和Kispeptin，之所以选择它们，是因为这些下丘脑基因以性别二态的方式表达，它们在整个生命周期中经历了强劲的变化，而且因为在生命早期发育期间暴露于外源雌激素扰乱了它们的基因表达，扰乱了生殖发育和衰老。目的1检测DNA甲基化的表观遗传修饰是否影响下丘脑区Era和Kispeptin基因的编程表达。目的2将验证组蛋白乙酰化的表观遗传事件对于成年期和生殖衰老过程中这些基因的激活和表达的维持是重要的假说。实验将在雄性和雌性大鼠身上进行，按性别和年龄进行比较。一小部分动物将暴露在产前雌激素中，这会扰乱生殖过程，加速生殖衰老。作为一个整体，这些研究将提供关于组织和维持正常生殖功能所需的关键下丘脑基因的新的表观遗传学分子数据，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.