insight - Cell Biology - # Chromosome stiffness in mouse oocytes during meiosis and aging

Dynamics of Chromosome Stiffness Across Cell Cycle Stages and Aging in Mouse Oocytes

Q: How do the changes in chromosome stiffness across cell cycle stages and with aging impact the fidelity of chromosome segregation during meiosis?

The changes in chromosome stiffness across cell cycle stages and with aging can have significant implications for the fidelity of chromosome segregation during meiosis. During meiosis, the proper alignment and segregation of chromosomes are crucial for the generation of genetically diverse gametes. The dynamic regulation of chromosome stiffness plays a role in ensuring the accurate separation of homologous chromosomes and sister chromatids during meiosis. In the context of cell cycle stages, the differences in chromosome stiffness between mitotic and meiotic cells, as well as between meiosis I and meiosis II, suggest distinct mechanisms at play during chromosome segregation. For example, the higher stiffness of chromosomes in meiotic cells, particularly in meiosis I, may be necessary to withstand the forces exerted during homologous chromosome pairing, synapsis, and recombination. This increased stiffness could help prevent chromosome breakage and ensure proper alignment of homologous chromosomes. With aging, the observed increase in chromosome stiffness in aged oocytes may impact the fidelity of chromosome segregation during meiosis. Higher chromosome stiffness could potentially lead to difficulties in chromosome alignment and separation, increasing the likelihood of errors such as nondisjunction or lagging chromosomes. These errors can result in aneuploidy, where gametes have an abnormal number of chromosomes, leading to developmental abnormalities or infertility. Overall, changes in chromosome stiffness across cell cycle stages and with aging can influence the mechanical properties of chromosomes, affecting their behavior during meiosis and ultimately impacting the fidelity of chromosome segregation.

Q: What other factors, besides cohesin and DNA integrity, might contribute to the dynamic regulation of chromosome stiffness?

In addition to cohesin proteins and DNA integrity, several other factors may contribute to the dynamic regulation of chromosome stiffness: Histone Modifications: Post-translational modifications of histones, such as methylation and acetylation, can alter chromatin structure and influence chromosome stiffness. Changes in histone modifications can impact the compaction of chromatin fibers and, consequently, the overall stiffness of chromosomes. Nuclear Proteins: Nuclear proteins play a role in organizing chromatin and regulating chromosome structure. Alterations in the levels or activities of nuclear proteins, especially those involved in chromatin remodeling, can affect chromosome stiffness. Microtubule Dynamics: The interaction between chromosomes and microtubules during cell division can influence chromosome stiffness. Dynamic changes in microtubule attachments and forces exerted on chromosomes can impact their mechanical properties. Cellular Metabolism: Cellular metabolism and energy levels can affect chromatin organization and chromosome stiffness. Metabolic changes, such as fluctuations in ATP levels, can influence the activity of chromatin-modifying enzymes and impact chromosome structure. Epigenetic Regulators: Epigenetic factors, including DNA methylation patterns and non-coding RNAs, can modulate chromatin structure and gene expression, potentially affecting chromosome stiffness. By considering these additional factors, researchers can gain a more comprehensive understanding of the complex mechanisms that regulate chromosome stiffness and its impact on cellular processes.

Q: Could the insights gained from studying chromosome stiffness be leveraged to develop new strategies for improving oocyte quality and fertility in older individuals?

The insights gained from studying chromosome stiffness have the potential to inform the development of new strategies for improving oocyte quality and fertility in older individuals. Here are some ways in which this knowledge could be applied: Diagnostic Tools: Chromosome stiffness measurements could serve as a diagnostic tool to assess the quality of oocytes in older individuals. By evaluating the stiffness of chromosomes, clinicians could identify potential issues that may affect fertility and reproductive outcomes. Therapeutic Interventions: Understanding the factors that influence chromosome stiffness, such as histone modifications or nuclear proteins, could lead to the development of targeted therapies to modulate chromosome properties in aging oocytes. By manipulating these factors, researchers may be able to enhance oocyte quality and improve fertility outcomes. Age-Related Interventions: Strategies aimed at preserving chromosome integrity and reducing age-related changes in chromosome stiffness could be explored. This may involve interventions to maintain DNA repair mechanisms, regulate histone modifications, or optimize nuclear protein levels to mitigate the effects of aging on oocyte quality. Reproductive Technologies: The knowledge of chromosome stiffness could also be integrated into assisted reproductive technologies (ART) to optimize oocyte selection and improve success rates in older individuals undergoing fertility treatments. By considering chromosome mechanics in the selection of oocytes for in vitro fertilization, clinicians may enhance the chances of successful pregnancies. Overall, leveraging the insights from studying chromosome stiffness could open up new avenues for enhancing oocyte quality and fertility in older individuals, offering potential benefits for reproductive health and assisted reproduction.

Core Concepts

Chromosome stiffness varies dynamically across different cell cycle stages and with aging, independent of meiosis-specific cohesin proteins.

Abstract

This study investigated the stiffness of chromosomes isolated from mouse oocytes at different cell cycle stages and with aging. The key findings are:

Chromosomes from metaphase I (MI) oocytes are about 10 times stiffer than mitotic chromosomes, while chromosomes from metaphase II (MII) oocytes have relatively low stiffness.
The meiosis-specific cohesin proteins REC8, STAG3, and RAD21L do not contribute significantly to the high chromosome stiffness observed in MI oocytes.
Chromosomes from aged MI oocytes (48 weeks old) exhibit higher stiffness compared to young MI oocytes (3-4 weeks old), despite the age-related decrease in cohesin levels.
Inducing DNA damage in MI oocytes using etoposide reduces chromosome stiffness, suggesting that DNA integrity, rather than cohesin levels, is a key factor regulating chromosome stiffness.

The results demonstrate the dynamic and complex nature of chromosome stiffness, which is influenced by the cell cycle stage and aging, but not solely dependent on meiosis-specific cohesin proteins. This provides important insights into the structural organization and mechanics of chromosomes during meiosis and aging.

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biorxiv.org

Stats

The Young's modulus (a measure of stiffness) of chromosomes was:

Mitotic cells: 340 ± 80 Pa
MI oocytes: 3790 ± 700 Pa
MII oocytes: 670 ± 130 Pa
WT spermatocytes at prophase I: 2710 ± 610 Pa
Rec8-/- spermatocytes at prophase I: 2580 ± 620 Pa
Stag3-/- spermatocytes at prophase I: 2240 ± 210 Pa
Rad21l-/- spermatocytes: 2050 ± 370 Pa
48 weeks old MI oocytes: 8150 ± 1590 Pa
3-4 weeks old MI oocytes: 3790 ± 700 Pa
50 μg/ml etoposide-treated MI oocytes: 1710 ± 430 Pa

Quotes

"Chromosome stiffness from MI mouse oocytes was 3790 ± 700 Pa, which was significantly higher than that of MEF chromosomes."
"The Young's Modulus of MII oocytes was 670 ± 130 Pa, while that of MI oocytes is 3790 ± 700 Pa (P<0.001)."
"We did not observe a significant difference in chromosome stiffness between wild type (WT) control and Rec8-/-, Stag3-/-, or Rad21l-/- mutants."
"Chromosomes from old MI oocytes were much stiffer than those from young MI oocytes (8150 ± 1590 Pa in old MI oocyte versus 3790 ± 700 Pa in young MI oocyte, P=0.0150)."
"The stiffness of the chromosomes from etoposide-treated MI oocytes was significantly lower than that from the control MI oocytes (1710 ± 430 Pa versus 3780 ± 700 Pa, respectively, P=0.0245)."

Key Insights Distilled From

Cell-cycle and Age-Related Modulations in Mouse Chromosome Stiffness

by Liu,N., Qian... at www.biorxiv.org 03-11-2024

https://www.biorxiv.org/content/10.1101/2024.03.06.583771v1

Deeper Inquiries

How do the changes in chromosome stiffness across cell cycle stages and with aging impact the fidelity of chromosome segregation during meiosis?

The changes in chromosome stiffness across cell cycle stages and with aging can have significant implications for the fidelity of chromosome segregation during meiosis. During meiosis, the proper alignment and segregation of chromosomes are crucial for the generation of genetically diverse gametes. The dynamic regulation of chromosome stiffness plays a role in ensuring the accurate separation of homologous chromosomes and sister chromatids during meiosis.
In the context of cell cycle stages, the differences in chromosome stiffness between mitotic and meiotic cells, as well as between meiosis I and meiosis II, suggest distinct mechanisms at play during chromosome segregation. For example, the higher stiffness of chromosomes in meiotic cells, particularly in meiosis I, may be necessary to withstand the forces exerted during homologous chromosome pairing, synapsis, and recombination. This increased stiffness could help prevent chromosome breakage and ensure proper alignment of homologous chromosomes.
With aging, the observed increase in chromosome stiffness in aged oocytes may impact the fidelity of chromosome segregation during meiosis. Higher chromosome stiffness could potentially lead to difficulties in chromosome alignment and separation, increasing the likelihood of errors such as nondisjunction or lagging chromosomes. These errors can result in aneuploidy, where gametes have an abnormal number of chromosomes, leading to developmental abnormalities or infertility.
Overall, changes in chromosome stiffness across cell cycle stages and with aging can influence the mechanical properties of chromosomes, affecting their behavior during meiosis and ultimately impacting the fidelity of chromosome segregation.

What other factors, besides cohesin and DNA integrity, might contribute to the dynamic regulation of chromosome stiffness?

In addition to cohesin proteins and DNA integrity, several other factors may contribute to the dynamic regulation of chromosome stiffness:

Histone Modifications: Post-translational modifications of histones, such as methylation and acetylation, can alter chromatin structure and influence chromosome stiffness. Changes in histone modifications can impact the compaction of chromatin fibers and, consequently, the overall stiffness of chromosomes.

Nuclear Proteins: Nuclear proteins play a role in organizing chromatin and regulating chromosome structure. Alterations in the levels or activities of nuclear proteins, especially those involved in chromatin remodeling, can affect chromosome stiffness.

Microtubule Dynamics: The interaction between chromosomes and microtubules during cell division can influence chromosome stiffness. Dynamic changes in microtubule attachments and forces exerted on chromosomes can impact their mechanical properties.

Cellular Metabolism: Cellular metabolism and energy levels can affect chromatin organization and chromosome stiffness. Metabolic changes, such as fluctuations in ATP levels, can influence the activity of chromatin-modifying enzymes and impact chromosome structure.

Epigenetic Regulators: Epigenetic factors, including DNA methylation patterns and non-coding RNAs, can modulate chromatin structure and gene expression, potentially affecting chromosome stiffness.

By considering these additional factors, researchers can gain a more comprehensive understanding of the complex mechanisms that regulate chromosome stiffness and its impact on cellular processes.

Could the insights gained from studying chromosome stiffness be leveraged to develop new strategies for improving oocyte quality and fertility in older individuals?

The insights gained from studying chromosome stiffness have the potential to inform the development of new strategies for improving oocyte quality and fertility in older individuals. Here are some ways in which this knowledge could be applied:

Diagnostic Tools: Chromosome stiffness measurements could serve as a diagnostic tool to assess the quality of oocytes in older individuals. By evaluating the stiffness of chromosomes, clinicians could identify potential issues that may affect fertility and reproductive outcomes.

Therapeutic Interventions: Understanding the factors that influence chromosome stiffness, such as histone modifications or nuclear proteins, could lead to the development of targeted therapies to modulate chromosome properties in aging oocytes. By manipulating these factors, researchers may be able to enhance oocyte quality and improve fertility outcomes.

Age-Related Interventions: Strategies aimed at preserving chromosome integrity and reducing age-related changes in chromosome stiffness could be explored. This may involve interventions to maintain DNA repair mechanisms, regulate histone modifications, or optimize nuclear protein levels to mitigate the effects of aging on oocyte quality.

Reproductive Technologies: The knowledge of chromosome stiffness could also be integrated into assisted reproductive technologies (ART) to optimize oocyte selection and improve success rates in older individuals undergoing fertility treatments. By considering chromosome mechanics in the selection of oocytes for in vitro fertilization, clinicians may enhance the chances of successful pregnancies.

Overall, leveraging the insights from studying chromosome stiffness could open up new avenues for enhancing oocyte quality and fertility in older individuals, offering potential benefits for reproductive health and assisted reproduction.