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RNA-Seq Facilitates Quantitative Analysis of Wild Type and Bnc1tr/tr oocyte Transcriptomes

ABSTRACT: Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, serious daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We have previously identified Basonuclin1 (BNC1) mutation from a large Chinese POI pedigree and find the targeted Bnc1 mutation mouse exhibites POI. In this study, we find that BNC1 plays a key role in the dynamic balance of ovarian reserve, and maintaining lipid metabolism and redox homeostasis in oocytes during follicular development. Deficiency of BNC1 results in premature follicular activation and accelerated follicular atresia, but doesn’t affect the ovarian primordial follicle reserve. Mechanistically, BNC1 targets the NF2-YAP pathway to trigger oocyte ferroptosis. Inhibition of ferroptosis significantly rescues POI. These findings uncover a novel pathologic mechanism of POI based on BNC1 deficiency and is the first report showing ferroptosis involved in oocyte death.

ORGANISM(S): Mus musculus

PROVIDER: GSE194194 | GEO | 2022/08/31

REPOSITORIES: GEO

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RNA-Seq Facilitates Quantitative Analysis of Wild Type and Bnc1tr/tr ovary Transcriptomes

Project description:Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, serious daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We have previously identified Basonuclin1 (BNC1) mutation from a large Chinese POI pedigree and find the targeted Bnc1 mutation mouse exhibites POI. In this study, we find that BNC1 plays a key role in the dynamic balance of ovarian reserve, and maintaining lipid metabolism and redox homeostasis in oocytes during follicular development. Deficiency of BNC1 results in premature follicular activation and accelerated follicular atresia, but doesn’t affect the ovarian primordial follicle reserve. Mechanistically, BNC1 targets the NF2-YAP pathway to trigger oocyte ferroptosis. Inhibition of ferroptosis significantly rescues POI. These findings uncover a novel pathologic mechanism of POI based on BNC1 deficiency and is the first report showing ferroptosis involved in oocyte death.

2022-08-31 | GSE194196 | GEO

Genome-wide maps of chromatin state in Wild Type mouse ovary

2022-08-31 | GSE194195 | GEO

Gene expression changes in ovaries of oocyte-specific conditional knockout of Ubc9 in juvenile mice

Project description:The reproductive lifespan in mammals is largely determined by the abundance and quality of oocytes residing within the primoridial ovarian follicular pool. Critical oocyte-expressed genes driving ovarian function have been identified, buta role for post-translational modifications, such as SUMOylation of these key factors is not well understood. Oocyte-specific genetic ablation of the sole E2 SUMOylation enzyme, UBC9, cause female sterility. Preantral and antral stage ovarian follicles are depleted by sexual maturity, and loss of the ovarian reserve in early adulthood causes premature ovarian failure, a condition associated with infertility in women. Gene expression changes indicate atered function of multiple POI candidate genes, including the transcription factors, NOBOX and SOHLH1. Together, these studies show that SUMOylation is required in the mammalian oocyte for regulating key genetic determinants of oocyte growth and differentiation.

2019-11-15 | GSE133179 | GEO

Transcriptome analysis during VCD exposure-induced POI in mice

Project description:4-vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure leading to POIs, which can seriously affect a woman's physical health and fertility. Investigating its pathogenic mechanisms can help provide guidance for the prevention of ovarian impairment and the treatment of POI. We built a mouse model of POI by intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. Then compared it with the control group at two time points, day 15 and day 30, including the comparison of phenotypic characteristics and differences in the transcriptome. We performed a comprehensive analysis of the differential genes identified and validated some key genes by RT-PCR. The results showed that sex hormone levels, follicle number and estrous cycle of VCD-induced POI mice were significantly affected at both day 15 and day 30. Regarding DEGs and enrichment results, the results obtained at day 15 were not as significant as those at day 30. Our results provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis play an important part in the process by which VCD affects ovarian function. Maybe it was due to impaired follicular development caused by VCD damage to the primordial follicular pool, and with the progression of time, the ovarian damage was aggravated, and it was gradually difficult to perform normal function.

2024-03-27 | GSE249151 | GEO

small non-coding RNA sequencing of human cumulus cells from patients with or without Diminished ovarian reserve

Project description:This group consist of human embryologists from the reproductive medical center for of the 1st affiliated hospital of Anhui Medical University. Our research is specifically focused on women ovarian reserve and the relevant female infertility. By deep sequencing, the current experiment determined the small non-coding RNA profile of cumulus cells from patients with or without diminished ovarian reserve undergoing controlled ovarian stimulation and in vitro fertilization treatment. Ovarian follicles, which are a densely-packed shell of granulosa cells that contains an immature or mature oocyte, are above all responsible for the development, maturation, and release of mature egg for fertilization. They are also responsible for synthesizing and secreting hormones that are essential for follicular development, menstrual and estrous cycle, maintenance of the reproductive tracts and their functions, development of female secondary sex characteristics, and metabolism. During folliculogenesis, ovarian granulosa cells surrounding the oocyte differentiate into mural granulosa cells, involved in gonadal steroidogenesis, and into cumulus cells, which are ovulated with the oocyte at ovulation. In the present study, we described the small non-coding RNA expression profile to characterize the ensemble of both known and novel ncRNAs expressed in cumulus cells from patients with or without Diminished ovarian reserve, by using high-throughput Solexa technology.

2015-11-20 | E-MTAB-3913 | biostudies-arrayexpress

Female Infertility: Primary ovarian insufficiency

Project description:<p>Premature ovarian failure, or primary ovarian insufficiency (POI) is a phenotype of diminished or absent ovarian function occurring in 1-2% of reproductive aged women. Most cases occur spontaneously. Evaluation of the gametes in women with POI is difficult and invasive. Practitioners must often rely on indirect biomarkers of ovarian function and oocyte health, making it difficult to identify patients who may benefit from therapies allowing them to achieve pregnancy utilizing their own oocytes. This study will generate exome sequences from POI patients in an effort to elucidate the causes of unexplained POI and to better understand the normal processes of ovarian aging. A better understanding of the genetics of ovarian function may lead to new non-invasive tools for managing women's reproductive health, and direct better use of existing biomarkers in diagnosis, screening and predicting clinical outcomes. </p>

| phs001174 | dbGaP

PRC1-mediated epigenetic programming is required to generate the ovarian reserve

Project description:The ovarian reserve defines the female reproductive lifespan, which in humans spans decades due to robust maintenance of meiotic arrest in oocytes residing in primordial follicles. Epigenetic reprogramming, including DNA demethylation, accompanies meiotic entry, but the chromatin changes that underpin the generation and preservation of ovarian reserves are poorly defined. We report that the Polycomb Repressive Complex 1 (PRC1) establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. PRC1 dysfuction causes depletion of the ovarian reserve and leads to premature ovarian failure. Our study demonstrates a fundamental role for PRC1-mediated gene silencing in female reproductive lifespan, and reveals a critical window of epigenetic programming required to establish ovarian reserve.

2022-06-26 | GSE184208 | GEO

The transcriptome of human oocytes is related to age and ovarian reserve.

Project description:Although it is well established that the ovarian reserve diminishes with increasing age, and that a woman’s age is correlated to lower oocyte quality, the interplay of a diminished reserve and age on oocyte developmental competence is not clear. After maturation, oocytes are mostly transcriptionally quiescent, and developmental competence prior to embryonic genome activation (EGA) relies on maternal RNA and proteins. Age and ovarian reserve both affects oocyte developmental competence, however, their relative importance in this process are difficult to tease out, as ageing is accompanied by a decrease in ovarian reserve. Oocytes store large quantities of RNA, including several noncoding transcripts (ncRNAs) involved in early development transcription and translation modulation. Despite the central role of ncRNAs in maternal to zygote transition, no characterization of the ncRNA transcriptome in human oocytes has been reported. This study aims at identifying how the human oocyte transcriptome changes across reproductive ages and ovarian reserve levels, with the goal of identifying candidate markers of developmental competence, and to assess the independent relevance of age and ovarian reserve in the changes of the transcriptome

2017-08-29 | GSE87201 | GEO

SRSF1 regulates primordial follicle formation and number determination during meiotic prophase I

Project description:Serine/arginine-rich splicing factor 1 (SRSF1; previously SF2/ASF) is a pivotal posttranscriptional regulator of gene expression in various biological processes. However, the physiological roles and mechanism of SRSF1 in mouse early-stage oocytes remain elusive. Here we show that SRSF1 is essential for primordial follicle formation and number determination during meiotic prophase I. The conditional knockout of Srsf1 in mouse oocytes impairs primordial follicle formation and leads to primary ovarian insufficiency (POI). Oocyte-specific genes (e.g., LHX8, NOBOX, SOHLH1, SOHLH2, FIGLA, KIT, JAGGED1, and RAC1) that regulate primordial follicle formation are suppressed in newborn Stra8-GFPCre Srsf1Fl/Fl (cKO) mouse ovaries. However, meiotic defects are the leading cause of abnormal primordial follicle formation. In cKO mouse ovaries, immunofluorescence results suggest that the failure of synapsis and the inability to undergo recombination result in fewer homologous DNA crossovers (COs). Moreover, SRSF1 directly binds and regulates the expression of the POI-related genes Six6os1 and Msh5 via alternative splicing to implement the meiotic prophase I program. Altogether, our data reveal a critical role of the SRSF1-mediated posttranscriptional regulatory mechanism in the mouse oocyte meiotic prophase I program, which provides a framework to elucidate molecular mechanisms of the posttranscriptional network underlying primordial follicle formation.

2023-02-06 | GSE198205 | GEO

HO-1 modulates ferroptosis via ROS-mediated mitochondrial dysfunction in cyclophosphamide -induced ovarian granulosa cells

Project description:Abnormal granulosa cells (GCs) death contributes to cyclophosphamide (CTX) -induced primary ovarian insufficiency (POI). To investigate the contribution of GCs in POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) are enriched in ferroptosis-related pathway, which is correlated with the upregulated Heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed that iron overload and disrupting ROS, including cytoROS, mtROS and lipROS homeostasis by HO-1 upregultion could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies the role of ROS in CTX-induced ferroptosis and highlighted the effect of HO-1 modulators of improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.

2023-10-30 | GSE243720 | GEO

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