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Age-associated increase in aneuploidy and changes in gene expression in mouse eggs.

ABSTRACT: An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60-70 weeks of age) display a 6-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that approximately 5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6-12 weeks of age) and that this fraction increases to approximately 33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the age-associated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation

ORGANISM(S): Mus musculus

PROVIDER: GSE11667 | GEO | 2008/06/07

SECONDARY ACCESSION(S): PRJNA106063

REPOSITORIES: GEO

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Transcription profiling of mouse oocytes to investigate age-associated increase in aneuploidy and changes in gene expression.

Project description:An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60-70 weeks of age) display a 6-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that approximately 5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6-12 weeks of age) and that this fraction increases to approximately 33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the age-associated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation Experiment Overall Design: We profiled the global gene expression in GV & MII oocyte by maternal aging, and identified the genes differentially expressed.

2008-06-18 | E-GEOD-11667 | biostudies-arrayexpress

Increased expression of BubR1 protects against aneuploidy in aging oocytes and extends reproductive lifespan

Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility. Examination of the effect of maternal aging on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 6 young (3 month) and 6 aging (12 month) female mice (3 oocytes per mice, 18 oocytes for each group).

2014-05-10 | E-GEOD-57482 | biostudies-arrayexpress

Increased expression of BubR1 protects against aneuploidy in aging oocytes and extends reproductive lifespan

2014-05-10 | GSE57482 | GEO

Translatome of aged mouse NEBD – stage oocytes determined using a new polysomal profiling method

Project description:We provide complete translatome of mouse oocytes from aged females after the breakdown of nuclear envelope (NEBD). RNAseq of polysomal and non-polysomal RNA was determined by using a novel approach combining polysomal fractionation of 200 NEBD-staged oocytes in small SW55Ti centrifugation tubes in the absence of any external spike and qRT-PCR analysis of ribosomal RNA in collected fractions. We compared these data to the translatome of same stage oocytes from young females (GSE121358). We report that genome-wide translatome profiling reveals considerable numbers of transcripts that are differentially translated in oocytes obtained from aged compared to young females. Additionally, we show the majority of aberrantly translated mRNAs in older oocytes have roles associated with cell cycle regulation. Indeed, we demonstrate the differential translation rates of four specific maternal age related transcripts (Sgk1, Castor1, Aire and Eg5) are associated with distinct localization patterns around the newly forming meiotic spindle.

2021-01-01 | GSE151836 | GEO

Genome-wide maps of small RNA transcription in young and old mouse oocytes

Project description:We report the abundance of different small RNAs in oocytes of young (8 weeks old) and older (9 months old) mouse females

2020-11-05 | GSE159789 | GEO

Ovulation suppression protects against chromosomal abnormalities in mouse eggs at advanced maternal age

Project description:The frequency of egg aneuploidy and trisomic pregnancies increases with maternal age. To what extent individual approaches can delay the “maternal age effect” is unclear since multiple causes contribute to chromosomal abnormalities in mammalian eggs. We propose that ovulation frequency determines the physiological ageing of oocytes, a key aspect of which is the ability to accurately segregate chromosomes and produce euploid eggs. To test this hypothesis, ovulations were reduced using successive pregnancies, hormonal contraception and a pre-pubertal knockout mouse model, and the effects on chromosome segregation and egg ploidy were examined. We show that each intervention reduces chromosomal abnormalities in eggs of aged mice, suggesting that ovulation reduction delays oocyte ageing. The protective effect can be partly explained by retention of chromosomal Rec8-cohesin that maintains sister chromatid cohesion in meiosis. In addition, single-nucleus Hi-C (snHi-C) revealed a deterioration in 3D chromatin structure including an increase in extruded loop sizes in long-lived oocytes. Artificial cleavage of Rec8 is sufficient to increase extruded loop sizes, suggesting that cohesin complexes maintaining cohesion restrict loop extrusion. These findings suggest that ovulation suppression protects against Rec8 loss, thereby maintaining both sister chromatid cohesion and 3D chromatin structure and promoting production of euploid eggs. We conclude that the “maternal age effect” can be delayed in mice. An implication of this work is that long-term ovulation-suppressing conditions can potentially reduce the risk of Down’s syndrome pregnancies at advanced maternal age.

2021-07-27 | GSE171159 | GEO

Ovulation suppression prevents the increase in egg aneuploidy with maternal age in mammals

Project description:Multiple mechanisms likely contribute to the increase in chromosome missegregation that leads to production of aneuploid eggs and fetuses at advanced maternal age. It is therefore considered unlikely that a single approach could prevent age-related egg aneuploidy. Here we show using three independent approaches that ovulation reduction is sufficient to prevent egg aneuploidy in aged mammals. To gain insights into the mechanism underlying the rescue in egg aneuploidy, we show that ovulation suppression correlates with retention of chromosomal Rec8-cohesin, implying that ovulations are linked to cohesin deterioration. Moreover, we discovered that ageing alters 3D chromatin organization by single-nucleus Hi-C (snHi-C). Extruded loops increase in size with age and this is retarded by ovulation reduction. We conclude that reducing ovulations leads to retention of chromosomal Rec8, which maintains interphase chromatin structure and promotes chromosome segregation and production of euploid eggs. Importantly, our data suggest that ovulation itself contributes to the maternal age effect. This work provides the first experimental evidence that progesterone treatment reduces egg aneuploidy and suggests that hormonal contraception can reduce the risk of trisomic pregnancies like Down’s syndrome at advanced maternal age.

2021-04-01 | GSE130585 | GEO

DPAGT1-Mediated Protein N-Glycosylation Is Indispensable for Oocyte and Follicle Development in Mice

Project description:Posttranslational modification of proteins by N-linked glycosylation is crucial for many life processes. However, the exact contribution of N-glycosylation to mammalian female reproduction remains largely undefined. Here, DPAGT1, the enzyme that catalyzes the first step of protein N-glycosyation, is identified to be indispensable for oocyte development in mice. A recessive missense mutation (c. 497A>G; p. Asp166Gly) of Dpagt1 causes female subfertility without grossly affecting other functions. Mutant females ovulate fewer eggs owing to defects of follicular development beyond the late secondary stage. Oocytes ovulated by mutants carry a thin and fragile zona pellucida, and display poor developmental competence after fertilization in vitro. Moreover, completion of the first meiosis is accelerated in mutant oocytes, which is coincident with the elevation of aneuploidy. Mechanistically, transcriptomic analysis reveals the downregulation of a number of transcripts essential for oocyte meiotic progression and preimplantation development (e.g., Pttgt1, Esco2, Orc6, and Npm2) in mutant oocytes, which could account for the defects observed. Furthermore, conditional knockout (CKO) of Dpagt1 in oocytes recapitulates the phenotypes observed in Dpagt1 mutant females, and causes complete infertility. Taken together, these data indicate that protein N-glycosylation in oocytes is essential for female fertility in mammals by specific control of oocyte development.

2021-09-09 | PXD018531 | Pride

Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis [scRNA-seq]

Project description:Advancing maternal age causes a progressive reduction in fertility. The decline in developmental competence of the oocyte with age is likely to be a consequence of multiple contributory factors. Loss of epigenetic quality of the oocyte should be considered as one factor, as epigenetic errors could impair early developmental events or programme adverse outcomes in offspring that manifest only later in life. Here, we undertake joint profiling of the transcriptome and DNA methylome in individual oocytes from reproductively young and old female mice. We find reduced complexity as well as increased variance in the transcriptome in oocytes from aged females. This heterogeneity is reflected in the identification of discrete sub-populations of oocytes, including those with a transcriptome characteristic of oocytes with immature chromatin configuration, as well as those with a young-like transcriptome. Oocytes from older females had on average reduced CpG methylation, but the characteristic bimodal methylation landscape of the oocyte was preserved. Germline differentially methylated regions of imprinted genes were appropriately methylated irrespective of age. For the majority of differentially expressed transcripts, the absence of correlated methylation changes suggests a post-transcriptional basis for most age-related effects on the transcriptome. However, we did find differences in gene-body methylation at which there were corresponding changes in gene expression, indicating age-related effects on transcription that translate into methylation differences. Interestingly, oocytes varied in expression and methylation of these genes, which could contribute to variable competence of oocytes or penetrance of maternal age-related phenotypes in offspring.

2020-11-20 | GSE154368 | GEO

Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis [scBS-seq]

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