Oogenesis: Ageing Oocyte Chromosomes Rely on Amazing Protein Stability

Tóth, Attila; Jessberger, Rolf

doi:10.1016/j.cub.2016.02.059

Cited by 4 publications

(6 citation statements)

References 18 publications

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“…Advanced maternal age has been shown to be directly related to an increased rate of aneuploidies, with cohesin loss and centromeric abnormalities being the most studied underlying causes (Tachibana-Konwalski et al, 2010;Burkhardt et al, 2016;Smoak et al, 2016;Toth and Jessberger, 2016;Gruhn et al, 2019;Zielinska et al, 2019). Strikingly, in our data, among the top hits of biological processes affected by maternal age in IVM-MII oocytes are chromosome and chromatid segregation-related terms (Supplementary Table 5).…”

Section: Maturation Stage Is the Main Differentiator Of Oocyte Transcmentioning

confidence: 59%

“…In this study we have shown that age as well as BMI affect key pathways at the RNAlevel, which are involved in oocyte maturation and function such as chromosome segregation, mitochondria, RNA-metabolism and translation. While many age-related oocyte defects, as for example chromosome segregation errors, have been attributed to low protein turnover during meiotic arrest (Tachibana-Konwalski et al, 2010;Burkhardt et al, 2016;Smoak et al, 2016;Toth and Jessberger, 2016;Gruhn et al, 2019;Zielinska et al, 2019), it has been less appreciated that as well the transcripts related to centromeric-or cohesin-associated factors are misregulated during oocyte ageing. Maturing oocytes go through a dramatic rewiring of gene expression dynamics, which includes phases of global transcriptional and translational repression and selective RNA polyadenylation and RNA degradation (Clarke, 2018;De La Fuente, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…It is unclear to which degree proteins like REC8 and CENP-A are turned over in human oocytes over time. Furthermore, studies in mouse and human suggest that age-related chromosome segregation errors could be due to gradual loss of cohesion and kinetochore compaction (Burkhardt et al, 2016;Smoak et al, 2016;Toth and Jessberger, 2016;Gruhn et al, 2019;Zielinska et al, 2019) and altered microtubule dynamics leading to non-disjunction events (Nakagawa and FitzHarris, 2017). In addition, mitochondria-related defects (May-Panloup et al, 2016;Almansa-Ordonez et al, 2020) and epigenetic changes affecting gene expression (Ge et al, 2015;Chamani and Keefe, 2019) contribute to the agerelated oocyte quality decline.…”

Section: Introductionmentioning

confidence: 99%

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Single cell analysis reveals the impact of age and maturation stage on the human oocyte transcriptome

Llonch

Barragán²,

Nieto

et al. 2020

Preprint

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Study questionTo which degree does maternal age affect the transcriptome of human oocytes at the germinal vesicle (GV) stage or at metaphase II after maturation in vitro (IVM-MII)?Summary answerWhile the oocytes’ transcriptome is predominantly determined by maturation stage, transcript levels of genes related to chromosome segregation, mitochondria and RNA processing are affected by age after in vitro maturation of denuded oocytes.What is known alreadyFemale fertility is inversely correlated with maternal age due to both a depletion of the oocyte pool and a reduction in oocyte developmental competence. Few studies have addressed the effect of maternal age on the human mature oocyte (MII) transcriptome, which is established during oocyte growth and maturation, and the pathways involved remain unclear. Here, we characterize and compare the transcriptomes of a large cohort of fully grown GV and IVM-MII oocytes from women of varying reproductive age.Study design, size, durationIn this prospective molecular study, 37 women were recruited from May 2018 to June 2019. The mean age was 28.8 years (SD=7.7, range 18-43). A total of 72 oocytes were included in the study at GV stage after ovarian stimulation, and analyzed as GV (n=40) and in vitro matured oocytes (IVM-MII; n=32).Participants/materials, setting, methodsDenuded oocytes were included either as GV at the time of ovum pick-up or as IVM-MII after in vitro maturation for 30 hours in G2™ medium, and processed for transcriptomic analysis by single-cell RNA-seq using the Smart-seq2 technology. Cluster and maturation stage marker analysis were performed using the Seurat R package. Genes with an average fold change greater than 2 and a p-value < 0.01 were considered maturation stage markers. A Pearson correlation test was used to identify genes whose expression levels changed progressively with age. Those genes presenting a correlation value (R) >= |0.3| and a p-value < 0.05 were considered significant.Main results and the role of chanceFirst, by exploration of the RNA-seq data using tSNE dimensionality reduction, we identified two clusters of cells reflecting the oocyte maturation stage (GV and IVM-MII) with 4,445 and 324 putative marker genes, respectively. Next we identified genes, for which RNA levels either progressively increased or decreased with age. This analysis was performed independently for GV and IVM-MII oocytes. Our results indicate that the transcriptome is more affected by age in IVM-MII oocytes (1,219 genes) than in GV oocytes (596 genes). In particular, we found that genes involved in chromosome segregation and RNA splicing significantly increase in transcript levels with age, while genes related to mitochondrial activity present lower transcript levels with age. Gene regulatory network analysis revealed potential upstream master regulator functions for genes whose transcript levels present positive (GPBP1, RLF, SON, TTF1) or negative (BNC1, THRB) correlation with age.Limitations, reasons for cautionIVM-MII oocytes used in this study were obtained after in vitro maturation of denuded GV oocytes, therefore, their transcriptome might not be fully representative of in vivo matured MII oocytes.The Smart-seq2 methodology used in this study detects polyadenylated transcripts only and we could therefore not assess non-polyadenylated transcripts.Wider implications of the findingsOur analysis suggests that advanced maternal age does not globally affect the oocyte transcriptome at GV or IVM-MII stages. Nonetheless, hundreds of genes displayed altered transcript levels with age, particularly in IVM-MII oocytes. Especially affected by age were genes related to chromosome segregation and mitochondrial function, pathways known to be involved in oocyte ageing. Our study thereby suggests that misregulation of chromosome segregation and mitochondrial pathways also at the RNA-level might contribute to the age-related quality decline in human oocytes.Study funding/competing interest(s)This study was funded by the AXA research fund, the European commission, intramural funding of Clinica EUGIN, the Spanish Ministry of Science, Innovation and Universities, the Catalan Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and by contributions of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and to the “Centro de Excelencia Severo Ochoa”.The authors have no conflict of interest to declare.

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Section: Maturation Stage Is the Main Differentiator Of Oocyte Transcmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Single cell analysis reveals the impact of age and maturation stage on the human oocyte transcriptome

Llonch

Barragán²,

Nieto

et al. 2020

Preprint

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“…If centromere proteins are loaded once per cell cycle, they would have to be maintained for a long time before kinetochores are assembled and cell division commences [28]. Cohesins, for example, are loaded during S-phase and deteriorate with age, causing aneuploidy in older mothers [29, 30]. However, CENP-A nucleosomes in the mouse are stable and do not need to be maintained during meiotic prophase [28].…”

Section: Introductionmentioning

confidence: 99%

A Dynamic population of prophase CENP-C is required for meiotic chromosome segregation

Fellmeth

Sturm

Jang

et al. 2023

Preprint

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The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in Drosophila, which replaces canonical H3 at the centromeres. In Drosophila, CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. It is not clear, however, if these two functions require the same population of CENP-C. In Drosophila and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. We used RNAi knockdown, mutants, and transgenes to study the dynamics and function of CENP-C in meiosis. CENP-C that is incorporated into cells prior to the onset of meiosis is involved in centromere maintenance and CID recruitment. We found this is not sufficient for the other functions of CENP-C. Indeed, CENP-C is loaded during meiotic prophase, while CID and the chaperone CAL1 are not. CENP-C prophase loading is required for meiotic functions at two different times. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. Thus, CENP-C is one of the few proteins that links the function of the centromeres and kinetochores through the long prophase pause in oocytes.

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“…If centromere proteins are loaded once per cell cycle, they would have to be maintained for a long time before kinetochores are assembled and cell division commences [ 39 ]. Cohesins, for example, are loaded during S-phase and deteriorate with age, causing aneuploidy in older mothers [ 40 , 41 ]. CENP-A nucleosomes in mouse oocytes are stable and do not need to be maintained during meiotic prophase [ 39 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

A dynamic population of prophase CENP-C is required for meiotic chromosome segregation

Fellmeth,

Jang,

Persaud

et al. 2023

PLoS Genet

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The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in Drosophila. In Drosophila, CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. These two functions, however, happen at different times in the cell cycle. Furthermore, in Drosophila and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. We have investigated the dynamics of function of CENP-C during the extended meiotic prophase of Drosophila oocytes and found that maintaining high levels of CENP-C for metaphase I requires expression during prophase. In contrast, CID is relatively stable and does not need to be expressed during prophase to remain at high levels in metaphase I of meiosis. Expression of CID during prophase can even be deleterious, causing ectopic localization to non-centromeric chromatin, abnormal meiosis and sterility. CENP-C prophase loading is required for multiple meiotic functions. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. CENP-C is one of the few proteins identified in which expression during prophase is required for meiotic chromosome segregation. An implication of these results is that the failure to maintain recruitment of CENP-C during the extended prophase in oocytes would result in chromosome segregation errors in oocytes.

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Oogenesis: Ageing Oocyte Chromosomes Rely on Amazing Protein Stability

Cited by 4 publications

References 18 publications

Single cell analysis reveals the impact of age and maturation stage on the human oocyte transcriptome

Single cell analysis reveals the impact of age and maturation stage on the human oocyte transcriptome

A Dynamic population of prophase CENP-C is required for meiotic chromosome segregation

A dynamic population of prophase CENP-C is required for meiotic chromosome segregation

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