Spatiotemporal transcriptomic changes of human ovarian aging and the key regulatory role of FOXP1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE255690 | GEO | 2024/04/15
REPOSITORIES: GEO
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Project description:The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23–29 years) and four reproductively aged (ages 49–54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging.
2023-03-12 | GSE202601 | GEO
Project description:Ovarian aging leads to diminished fertility, dysregulated endocrine signaling, and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Around 35 years old, women experience a sharp decline in fertility, corresponding to declines in oocyte quality. However, the field lacks a cellular map of the transcriptomic changes in the aging ovary to identify drivers of ovarian decline. To fill this gap, we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with T and B lymphocyte proportions increasing most. We also discovered an age-related upregulation of alternative macrophage and downregulation of collagenase pathways in stromal fibroblasts. Overall, follicular cells (especially granulosa and theca) display stress response, immunogenic, and fibrotic signaling pathway inductions with aging. These changes are more exaggerated in the atretic granulosa cells but are also observed in healthy antral and preantral granulosa cells. Moreover, we did not observe age-related changes in markers of cellular senescence in any cellular population with advancing age, despite specific immune cells expressing senescence-related genes across both timepoints. This report raises several new hypotheses that could be pursued to elucidate mechanisms responsible for ovarian aging phenotypes.
2023-11-27 | GSE232309 | GEO
Project description:Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species and apoptosis were observed in granulosa cells from aged women. This study provides comprehensive understanding of the cell type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.
2020-01-28 | GSE130664 | GEO
Project description:Fertility preservation research in women today is increasingly taking advantage of bioengineering techniques to develop new biomimetic materials and solutions to safeguard ovarian cell function and microenvironment in vitro and in vivo. However, available data on the human ovary are limited and fundamental differences between animal models and humans are hampering researchers in their quest for more extensive knowledge of human ovarian physiology and key reproductive proteins that need to be preserved. We therefore turned to multi-dimensional label-free mass spectrometry to analyze human ovarian cortex, as it is a high-throughput and conclusive technique providing information on the proteomic composition of complex tissues like the ovary. In-depth proteomic profiling through two-dimensional liquid chromatography-mass spectrometry, western blot, histological and immunohistochemical analyses, and data mining helped us to confidently identify 1,508 proteins. Moreover, our method allowed us to chart the most complete representation so far of the ovarian matrisome, defined as the ensemble of extracellular matrix proteins and associated factors, including more than 80 proteins. In conclusion, this study will provide a better understanding of ovarian proteomics, with a detailed characterization of the ovarian follicle microenvironment, in order to enable bioengineers to create biomimetic scaffolds for transplantation and three-dimensional in vitro culture. By publishing our proteomic data, we also hope to contribute to accelerating biomedical research into ovarian health and disease in general
2018-02-27 | PXD008183 | Pride
Project description:Ovarian aging is characterized by the progressive depletion of primordial follicle reserve, leading to irregular patterns of ovulation and menopause. The basic mechanisms that underlie the ovarian aging and follicle decline is unknown. We sought to explore the role of cellular senescence and epigenomic mechanisms in ovarian aging. Here, we present the transcriptomic changes observed in the ovaries with age using the age groups 3mo, 6mo, 9mo and 12mo (n=5 per group except for 12mo which has an n=4). The age groups capture timepoints from sexual maturation to reproductive health decline.
2020-07-23 | GSE154890 | GEO
Project description:In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
2024-04-30 | GSE253194 | GEO
Project description:Our modern era is witnessing an increasing infertility rate worldwide. Although some of the causes can be attributed to our modern lifestyle (eg. persistent organic polluants, late pregnancy), our knowledge of the human ovarian tissue has remained limited and insufficient to reverse the infertility statistics. Indeed, all efforts have been focused on the endocrine and cellular function in support of the cell theory that dates back to the 18th century, while the human ovarian matrisome is still under-described. Therefore, hereby we provide the first systematic study focusing on the human ovarian matrisome and its remodeling during a woman lifetime, from prepuberty til menopause. We apply our matrisome tailored fractionation method, the DC-MaP strategy and mass spectrometry-based quantitative proteomics using TMT pro 16-plex isobaric labeling to delineate proteome-wide and ECM-specific shifts between prepubertal, reproductive-age and menopausal stages. Post-translational modifications, namely proline hydroxylation and advanced glycation ends products have also been detected at different intensities according to age. Matrisome age-biomarkers have been validated with lightsheet microscopy-based-3D imaging, following immunofluorescence and tissue clearing with an ovary-tailored protocol. We used machine learning and statistics to build a neural network that can predict predict the probability of a specific ovarian tissue matrisome to resemble to prepubertal, reproductive-age or menopausal tissue and potentially conclude its fertility potency or evaluate in the future the efficiency of ovarian rejuvenation treatments. We also used NLP medscan technology for advanced literature text-mining to predict all possible-connections between the extra- and intra-cellular compartments and how chemo-radiotherapy, known for its gonadotoxicity can also affect key matrisome proteins.This comprehensive proteomics analysis represents the ovarian proteomic codex and contributes to an improved understanding of the critical roles that ECM plays throughout ovarian life span. By publishing our proteomic data, we hope to open new avenues in fertility restoration, ovarian rejuvenation and reproductive tissue engineering
2022-04-06 | PXD025940 | Pride
Project description:Depletion of oocytes and follicles and reduced oocyte quality contribute to age-associated ovarian senescence and infertility. Telomere shortening and altered methylation make two major contributions to general aging. Resveratrol acts as anti-oxidant and Sirt1 activator to alleviate aging including reproductive aging. It remains elusive whether resveratrol can reprogram the aging epigenome. We sought to examine aging ovarian epigenome and the potential effects of resveratrol by combined analysis of telomere length, transcriptome and methylome mainly in oocytes and also in granulosa cells, two major cell types in the ovary.
2021-09-26 | GSE184636 | GEO
Project description:Depletion of oocytes and follicles and reduced oocyte quality contribute to age-associated ovarian senescence and infertility. Telomere shortening and altered methylation make two major contributions to general aging. Resveratrol acts as anti-oxidant and Sirt1 activator to alleviate aging including reproductive aging. It remains elusive whether resveratrol can reprogram the aging epigenome. We sought to examine aging ovarian epigenome and the potential effects of resveratrol by combined analysis of telomere length, transcriptome and methylome mainly in oocytes and also in granulosa cells, two major cell types in the ovary.
2021-09-26 | GSE184635 | GEO
Project description:The ovarian function decreases in parallel with aging. So do the quantity of follicles, which is about 1-2 million at birth, while only about 1000 primordial follicles are left at menopause. Folliculogenesis is vital for ovary function, no matter the synthesis of female hormones or ovulation, yet the mechanisms for its changing with increasing age are not fully understood. To further understand the age-related molecular changes in the process of folliculogenesis, we performed microarray gene expression profile analysis using total RNA extracted from young (9 weeks old) and old (32 weeks old) mouse ovarian secondary follicles. The results of our current microarray study revealed that there were 371 (≥2 fold, q-value ≤0.05) genes differentially expressed in which 174 genes were up-regulated and 197 genes were down-regulated in old mouse ovarian secondary follicles compared to young mouse ovarian secondary follicles. The gene ontology and KEGG pathway analysis of differentially expressed genes uncovered critical biological functions such as immune system process, aging, transcription, DNA replication, DNA repair, protein stabilization and apoptotic process were affected in the process of aging. The considerable changes in gene expression profile may have an adverse influence on follicle quality and folliculogenesis. Our study provided information on the processes that may contribute to age-related decline in ovarian function.
2019-04-25 | GSE121493 | GEO