Regulatory Landscape of the Aging Human Ovary

生殖老龄化是一个重大的健康、个人和社会问题，但卵巢老化受到的影响有限。 科学关注，即使在大型基因组调查项目中也是如此。卵巢老化影响不同的健康结局 女性包括寿命、心血管疾病、代谢综合征、神经退行性疾病和 各种类型的癌症。然而，卵巢老化、绝经时间和卵巢老化的分子机制 器官间反馈环仍然难以捉摸。作为人体最具活力的器官之一，卵巢 在整个生殖期都经历了重大的重塑。动态转录调控 卵母细胞及其周围细胞在老化过程中的相互作用尚不清楚。的目标是 这项提议是为了了解不同机构之间复杂相互作用背后的监管格局 卵巢中的细胞类型，并研究调节显著复合体的分子机制 生殖衰老的过程。我们将应用强大的单细胞(Sc)rna-seq和scatac-seq分析来 确定在不同卵巢细胞中改变的特定转录程序和受调控的增强子网络 老化过程中的类型或亚型。通过定义特定增强子在特定细胞类型中的作用，以及这些 随着年龄的增长而变化，我们的目标是了解调控因素和环境信号的身份 影响每种卵巢细胞类型的衰老。影响增强子选择和功能的遗传变异是一个主要的 个体间细胞特异性基因表达差异的决定因素。探讨其作用机制 通过改变的调控增强子环境通过许可的改变来促进卵巢老化 转录程序，我们将调查与绝经年龄相关的遗传变异的作用， 通过全基因组关联研究(GWAS)检测到，在卵巢过程中调节转录程序 衰老。特别是，我们希望为转录调控的遗传调控提供机械性的见解。 支持细胞颗粒细胞(GC)的关键稳态和炎症病理功能 通过对人类GC模型中的因果调节变量进行建模，在卵母细胞周围立即键入 不同于通过CRISPR基因编辑而被设计成携带因果变体的人类ESCs。

Reproductive aging is a major health, personal and societal issue, but ovarian aging has received limited scientific attention, even in large genomic survey projects. Ovarian aging influences diverse health outcomes in women including lifespan, cardiovascular disease, metabolic syndromes, neurodegenerative disorders and various types of cancer. Yet the molecular mechanisms underlying ovarian aging, timing of menopause and inter-organ feedback loops remain elusive. As one of the most dynamic organs in the human body, the ovary undergoes significant remodeling across the entire reproductive period. The dynamic transcriptional regulation of and interactions between oocytes and their surrounding cells during aging remain unknown. The objective of this proposal is to understand the regulatory landscapes underlying the complex interplay among the different cell types in the ovary and to investigate the molecular mechanisms that regulate the remarkably complex processes of reproductive aging. We will apply powerful single-cell (sc) RNA-seq and scATAC-seq analysis to define specific transcriptional programs and regulated enhancer networks that are altered in distinct ovarian cell types or subtypes during aging. By defining the roles of specific enhancers in specific cell types, and how these change with aging, we aim to understand the identities of the regulatory factors and environmental signals that impact aging in each ovarian cell type. Genetic variation affecting enhancer selection and function is a major determinant of differences in cell-specific gene expression between individuals. To investigate the mechanisms by which altered regulatory enhancer landscapes contribute to ovarian aging by licensing changes in transcriptional programs, we will investigate the roles of genetic variants associated with age at menopause, detected by genome-wide association studies (GWAS), in modulating transcription programs during ovarian aging. In particular, we hope to provide mechanistic insights into genetic modulation of transcriptional regulation of critical homeostatic and inflammatory pathological functions in the granulosa cells (GC), the supporting cell type immediately surrounding the oocyte, by modeling the causal regulatory variants in human GC models that are differentiated from human ESCs engineered to carry causal variants by CRISPR gene editing.