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，有循环的性类固醇激素，包括雌二醇。虽然性激素需要以年龄和性别依赖的方式调节生殖生命的转变，但其潜在机制尚不清楚。本研究的重点是阐明生物体内激素环境调节下丘脑基因表达的表观遗传分子机制，以确保生殖生理与生命阶段的协调。选择雌激素受体α (ER1)和kisspeptin，是因为这些下丘脑基因以两性二态的方式表达，它们在整个生命周期中经历强烈的变化，并且因为在生命早期发育过程中暴露于外源雌激素会扰乱它们的基因表达，扰乱生殖发育和衰老。目的1将测试DNA甲基化的表观遗传修饰是否影响下丘脑ER1的编程和kisspeptin基因的表达。目的2将验证组蛋白乙酰化的表观遗传事件对于这些基因在成年期和生殖衰老过程中的激活和维持表达很重要的假设。实验将在雄性和雌性大鼠中进行，根据性别和年龄进行比较。一部分动物将在产前接触雌二醇，这会扰乱生殖过程，加速生殖衰老。总的来说，这些研究将为下丘脑正常生殖功能所需的关键基因的组织和维持提供新的表观遗传学分子数据，并进一步阐明基因表达与激素环境之间的联系。

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.