Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single‐cell analysis

Castillo-Fernandez, Juan; Herrera-Puerta, E.; Demond, Hannah; Clark, Stephen J.; Hanna, Courtney W.; Hemberger, Myriam; Kelsey, Gavin

doi:10.1111/acel.13278

Cited by 37 publications

(37 citation statements)

References 72 publications

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“…A similar trend was observed with the hetero-dimer pair. Our results aligns with previous reports, where this bimodal distribution is a common feature reported in single-cell analysis of epigenetics, given the heterogeneous epigenetic content within a cell population ( Grosselin et al, 2019 , Castillo-Fernandez et al, 2020 ).…”

Section: Discussionsupporting

confidence: 93%

Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells

Sánchez

Xie

et al. 2022

Current Research in Toxicology

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Section: Discussionsupporting

confidence: 93%

Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells

Sánchez

Xie

et al. 2022

Current Research in Toxicology

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“…This suggests that young oocytes are far more robust with regards to protein quality control than older oocytes. These findings are well supported by transcriptomic and single cell RNA sequencing studies (Grøndahl et al, 2010;Barragán et al, 2017;Wang et al, 2020) that demonstrate the dramatic modulation of mammalian oocyte transcriptomes with age, with the potential for these age-related effects on transcription to result in methylation differences (Castillo-Fernandez et al, 2020). These transcriptomic resources will enhance our understanding of changes in proteostasis that contribute to aging.…”

Section: The Contribution Of Declining Proteostasis To Oocyte Agingmentioning

confidence: 68%

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

Cafe

Nixon

Ecroyd

et al. 2021

Front. Cell Dev. Biol.

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For fully differentiated, long lived cells the maintenance of protein homeostasis (proteostasis) becomes a crucial determinant of cellular function and viability. Neurons are the most well-known example of this phenomenon where the majority of these cells must survive the entire course of life. However, male and female germ cells are also uniquely dependent on the maintenance of proteostasis to achieve successful fertilization. Oocytes, also long-lived cells, are subjected to prolonged periods of arrest and are largely reliant on the translation of stored mRNAs, accumulated during the growth period, to support meiotic maturation and subsequent embryogenesis. Conversely, sperm cells, while relatively ephemeral, are completely reliant on proteostasis due to the absence of both transcription and translation. Despite these remarkable, cell-specific features there has been little focus on understanding protein homeostasis in reproductive cells and how/whether proteostasis is “reset” during embryogenesis. Here, we seek to capture the momentum of this growing field by highlighting novel findings regarding germline proteostasis and how this knowledge can be used to promote reproductive health. In this review we capture proteostasis in the context of both somatic cell and germline aging and discuss the influence of oxidative stress on protein function. In particular, we highlight the contributions of proteostasis changes to oocyte aging and encourage a focus in this area that may complement the extensive analyses of DNA damage and aneuploidy that have long occupied the oocyte aging field. Moreover, we discuss the influence of common non-enzymatic protein modifications on the stability of proteins in the male germline, how these changes affect sperm function, and how they may be prevented to preserve fertility. Through this review we aim to bring to light a new trajectory for our field and highlight the potential to harness the germ cell’s natural proteostasis mechanisms to improve reproductive health. This manuscript will be of interest to those in the fields of proteostasis, aging, male and female gamete reproductive biology, embryogenesis, and life course health.

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“…In the human female germline, maternal methylation imprints are established during later stages of oocyte growth and for some genes may not be completed until shortly before pronuclear fusion [37]. However, consistent with the mouse model [13], the vast majority of human oocytes from both "younger" and "older" females displayed correct oocyte imprinting patterns. This also largely excludes somatic cell contamination and technical artefacts.…”

Section: Limitationsmentioning

confidence: 89%

“…In the mouse model, the majority of oocytes of older females displayed reduced complexity and increased variation of the transcriptome, associated with reduced developmental potential compared to oocytes from younger animals. Interestingly, a limited number of "old" oocytes exhibited a "young-like" epigenome [ 13 ]. Single oocyte methylomes from aged mice displayed decreased global CpG methylation (of single-copy genes), whereas our results show increased rDNA methylation in aging mouse and human oocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, aggregation of meiotic double-stranded breaks [5], loss of homologous recombination proteins [6] and cohesins [7], accumulation of oxidative stress [8], and a severe bottle neck in mitochondrial DNA segregation [9] may contribute to the maternal age-related medical AGING problems. Transcriptome analyses revealed numerous age-related changes in oocyte gene expression including genes for cell cycle regulation, energy production, and other critical pathways [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Ribosomal DNA methylation in human and mouse oocytes increases with age

Potabattula¹,

Trapphoff²,

Dittrich

et al. 2022

Aging

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An age-dependent increase in ribosomal DNA (rDNA) methylation has been observed across a broad spectrum of somatic tissues and the male mammalian germline. Bisulfite pyrosequencing (BPS) was used to determine the methylation levels of the rDNA core promoter and the rDNA upstream control element (UCE) along with two oppositely genomically imprinted control genes (PEG3 and GTL2) in individual human germinal vesicle (GV) oocytes from 90 consenting women undergoing fertility treatment because of male infertility. Apart from a few (4%) oocytes with single imprinting defects (in either PEG3 or GTL2), the analyzed GV oocytes displayed correct imprinting patterns. In 95 GV oocytes from 42 younger women (26-32 years), the mean methylation levels of the rDNA core promoter and UCE were 7.4±4.0% and 9.3±6.1%, respectively. In 79 GV oocytes from 48 older women (33-39 years), methylation levels increased to 9.3±5.3% (P = 0.014) and 11.6±7.4% (P = 0.039), respectively. An age-related increase in oocyte rDNA methylation was also observed in 123 mouse GV oocytes from 29 4-16-months-old animals. Similar to the continuously mitotically dividing male germline, ovarian aging is associated with a gain of rDNA methylation in meiotically arrested oocytes. Oocytes from the same woman can exhibit varying rDNA methylation levels and, by extrapolation, different epigenetic ages.

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Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single‐cell analysis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 37 publications

References 72 publications

Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells

Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

Ribosomal DNA methylation in human and mouse oocytes increases with age

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