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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE171159 | GEO | 2021/07/27

REPOSITORIES: GEO

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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

Wapl-mediated release of Scc1-cohesin regulates chromosome structure and segregation in mouse oocytes

Project description:Cohesin is essential for genome folding and chromosome inheritance through cell divisions. In somatic cells, both of these functions are mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Scc1 is also expressed but neither required nor sufficient for cohesion, and its function in oocytes is unknown. Likewise, it is unknown whether Wapl regulates one or both cohesin complexes and chromosome segregation in mature oocytes. Using conditional mouse mutagenesis, we show that in meiosis I Wapl is required for proper chromosome segregation, predominantly releases Scc1-cohesin from chromosomes and promotes production of euploid eggs. Using single-nucleus Hi-C, we found that Scc1 is essential for chromatin loops and topologically associating domains (TADs) in oocytes. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but, unlike in mitotic cells, does not increase loop size. This implies that loop size has reached a maximum in oocytes, possibly because it is limited by barriers such as cohesive cohesin. We conclude that distinct cohesin complexes generate loops and cohesion in mammalian oocytes and propose that the same principle applies to all cell types and species.

2020-03-04 | GSE132264 | GEO

Rec8 cohesin-mediated loop-axis chromatin architecture is required for meiotic recombination

Project description:During meiotic prophase, cohesin-dependent axial structures are formed in the synaptonemal complex (SC). However, functional correlation between these structure formation and cohesion remains elusive. Here we examined formation of the cohesin-dependent axial structure in fission yeast, which forms atypical SCs composed of linear elements (LinEs) resembling the lateral elements of SC but lacking the central elements, and found that Rec8 cohesin is crucial for the formation of the loop-axis structure within the atypical SC. Furthermore, the Rec8-mediated loop-axis structure is formed in the absence of LinEs, and provides a structural platform for aligning homologous chromosomes. We also succeeded to identify a rec8 mutant that lost the ability of assembling the loop-axis structure without losing cohesion. Remarkably, this mutant showed defects in LinE assembly, resulting in great reduction of meiotic recombination. Collectively, our results demonstrate an essential role of the Rec8-dependent loop-axis structure in LinE assembly, facilitating meiotic recombination.

2022-04-27 | GSE192516 | GEO

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

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

| PRJNA718570 | ENA

DNA double-strand breaks regulate the cleavage-independent release of Rec8-cohesin during yeast meiosis

Project description:The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA double-strand breaks (DSBs). Here, by genome-wide binding analysis of the meiotic cohesin with Rec8 as a kleisin, we found that Rec8 shows dynamic localization from middle to late meiotic prophase I with cleavage-independent global dissociation along chromosomes, driven by meiotic DSB formation. Each Rec8 binding site on the chromosome axis follows distinct dynamics with dissociation and association. Centromeres also showed reduced Rec8 binding in late prophase I relative to mid-prophase I, implying chromosome remodeling of the regions. Rec8 dissociation profile per chromosome is largely correlated with meiotic DSB density. Indeed, the spo11 mutant deficient in meiotic DSB formation did not show the cleavage-independent dissociation of Rec8 in late meiotic prophase I. These suggest the presence of a regulatory pathway for global Rec8-cohesin dynamics in response to meiotic DSBs.

2023-12-31 | GSE224074 | GEO

The transcriptomic profile of human microvascular endothelial cells after exposure to preeclamptic or normotensive third trimester trophoblast debris

Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10 µm) is referred to as trophoblast debris in this study. We have shown in the past that trophoblast debris from first trimester can contribute to maternal cardiovascular physiological adaptations. This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to preeclmaptic and normotensive trophoblast debris. Primeview human gene expression arrays were used to probe transcriptomic changes in human microvascular endothelial cells after exposure to preeclmaptic or normotensive trophoblast debris for 21 hours

2019-08-22 | GSE86032 | GEO

Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I

Project description:Segregation of homologous maternal and paternal centromeres to opposite poles during meiosis I depends on post-replicative crossing over between homologous non-sister chromatids, which creates chiasmata and therefore bivalent chromosomes. Destruction of sister chromatid cohesion along chromosome arms due to proteolytic cleavage of cohesin's Rec8 subunit by separase resolves chiasmata and thereby triggers the first meiotic division. This produces univalent chromosomes, the chromatids of which are held together by centromeric cohesin that has been protected from separase by shugoshin (Sgo1/MEI-S332) proteins. Here we show in both fission and budding yeast that Sgo1 recruits to centromeres a specific form of protein phosphatase 2A (PP2A). Its inactivation causes loss of centromeric cohesin at anaphase I and random segregation of sister centromeres at the second meiotic division. Artificial recruitment of PP2A to chromosome arms prevents Rec8 phosphorylation and hinders resolution of chiasmata. Our data are consistent with the notion that efficient cleavage of Rec8 requires phosphorylation of cohesin and that this is blocked by PP2A at meiosis I centromeres. Keywords: ChIP-chip, Mitosis, Meiosis, Cell cycle, Saccharomyces cerevisiae, Chromosome VI tiling array, Sgo1, Pp2A, Cse4, Ndc10, Rts1, Rec8

2006-05-10 | GSE4791 | GEO

Endothelial cell response to trophoblastic debris

Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae

2016-08-21 | GSE69996 | GEO

Role of H3.3 residues in chromatin assembly and cell fate at the maternal-to-embryo transition

Project description:HISRainbow mice were used to obtain mosaic ovaries for transcriptome analysis of MII eggs expressing H3.3-eGFP, H3.3R26K-eCFP, or H3.3K27R-mCherry. Results provide comparison of eggs with different genotypes and insight into mechanism of how resting oocytes are selected for ovulation.

2016-12-01 | GSE79580 | GEO

Placental Transcriptomes in the Common Aneuploidies Reveal Critical Regions on the Trisomic Chromosomes and Genome-Wide Effects

Project description:We profiled gene expression at the maternal-fetal interface during the second trimester of pregnancy (13-22 wks) in trisomy 13 (T13; Patau syndrome, n = 4), trisomy 18 (T18; Edwards syndrome, n = 4), trisomy 21 (T21; Down syndrome, n = 8), and in euploid pregnancies (n = 4). FISH confirmed the ploidy of the samples. Global transcriptional profiling identified differentially expressed transcripts (? 2-fold) in T21 (n = 160), T18 (n = 80), and T13 (n = 125). The majority were upregulated. Unexpectedly, most of the misexpressed genes were not located on the relevant trisomic chromosome, suggesting genome-wide dysregulation. A much smaller proportion of the differentially expressed transcripts were encoded on the aneuploid chromosome, also implicating gene dosage (1-5). In T21, <10% of the genes were transcribed from that chromosome, all but one from the Down syndrome critical region (21q21-22), which is postulated to play an important role in the clinical phenotype. For T13 and T18, a higher proportion of the overexpressed genes were located on the trisomic chromosome. In T13, 15% of the upregulated genes were on the affected chromosome; 15 resided on the long arm, 13q11-14. In T18, the percentage increased to 24, 15 of which were also located on the long arm (18q11-22). Our data suggested that the placental (and possibly fetal) phenotypes that are associated with T13, T18 and T21 are driven by the combined effects of genome-wide phenomena and increased gene dosage from critical regions of the triploid chromosome. We profiled gene expression at the maternal-fetal interface during the second trimester of pregnancy (13-22 wks) in trisomy 13 (T13; Patau syndrome, n = 4), trisomy 18 (T18; Edwards syndrome, n = 4), trisomy 21 (T21; Down syndrome, n = 8), and in euploid pregnancies (n = 4). FISH confirmed the ploidy of the samples.

2015-06-23 | E-GEOD-70102 | biostudies-arrayexpress

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