Review

Authors: Zaida Sarrate, Mireia Solé, Francesca Vidal...

The production of functional spermatozoa through spermatogenesis requires a spatially and temporally highly regulated gene expression pattern, which in case of alterations, leads to male infertility. Changes of gene expression by chromosome anomalies, gene variants, and epigenetic alterations have been described as the main genetic causes of male infertility. Recent molecular and cytogenetic approaches have revealed that higher order chromosome positioning is essential for basic genome functions, including gene expression. This review addresses this issue by exposing well-founded evidences which support that alterations on the chromosome topology in spermatogenetic cells leads to defective sperm function and could be considered as an additional genetic cause of male infertility.

Topics: Chromosome Aberrations; Chromosome Positioning; Humans; Infertility, Male; Male; Spermatogenesis

PubMed: 30229502
DOI: 10.1007/s10815-018-1313-3

Authors: Elvira Nikalayevich, Gaëlle Letort, Ghislain de Labbey...

The cortex controls cell shape. In mouse oocytes, the cortex thickens in an Arp2/3-complex-dependent manner, ensuring chromosome positioning and segregation. Surprisingly, we identify that mouse oocytes lacking the Arp2/3 complex undergo cortical actin remodeling upon division, followed by cortical contractions that are unprecedented in mammalian oocytes. Using genetics, imaging, and machine learning, we show that these contractions stir the cytoplasm, resulting in impaired organelle organization and activity. Oocyte capacity to avoid polyspermy is impacted, leading to a reduced female fertility. We could diminish contractions and rescue cytoplasmic anomalies. Similar contractions were observed in human oocytes collected as byproducts during IVF (in vitro fertilization) procedures. These contractions correlate with increased cytoplasmic motion, but not with defects in spindle assembly or aneuploidy in mice or humans. Our study highlights a multiscale effect connecting cortical F-actin, contractions, and cytoplasmic organization and affecting oocyte quality, with implications for female fertility.

Topics: Humans; Female; Animals; Mice; Spindle Apparatus; Oocytes; Cytoplasm; Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Meiosis; Mammals

PubMed: 38387459
DOI: 10.1016/j.devcel.2024.01.027

Authors: Marta Olszewska, Ewa Wiland, Nataliya Huleyuk...

BACKGROUND

Non-random chromosome positioning has been observed in the nuclei of several different tissue types, including human spermatozoa. The nuclear arrangement of chromosomes can be altered in men with decreased semen parameters or increased DNA fragmentation and in males with chromosomal numerical or structural aberrations. An aim of this study was to determine whether and how the positioning of nine chromosome centromeres was (re)arranged in the spermatozoa of fathers and sons - carriers of the same reciprocal chromosome translocation (RCT).

METHODS

Fluorescence in situ hybridization (FISH) was applied to analyse the positioning of sperm chromosomes in a group of 13 carriers of 11 RCTs, including two familial RCT cases: t(4;5) and t(7;10), followed by analysis of eight control individuals. Additionally, sperm chromatin integrity was evaluated using TUNEL and Aniline Blue techniques.

RESULTS

In the analysed familial RCT cases, repositioning of the chromosomes occurred in a similar way when compared to the data generated in healthy controls, even if some differences between father and son were further observed. These differences might have arisen from various statuses of sperm chromatin disintegration.

CONCLUSIONS

Nuclear topology appears as another aspect of epigenetic genomic regulation that may influence DNA functioning. We have re-documented that chromosomal positioning is defined in control males and that a particular RCT is reflected in the individual pattern of chromosomal topology. The present study examining the collected RCT group, including two familial cases, additionally showed that chromosomal factors (karyotype and hyperhaploidy) have superior effects, strongly influencing the chromosomal topology, when confronted with sperm chromatin integrity components (DNA fragmentation or chromatin deprotamination).

Topics: Chromatin; Chromosomes, Human; Fathers; Humans; Karyotype; Male; Pedigree; Ploidies; Spermatozoa; Translocation, Genetic

PubMed: 30709354
DOI: 10.1186/s12920-018-0470-7

Authors: Cátia S Janota, Francisco J Calero-Cuenca, Judite Costa...

The nucleus is connected to the cytoskeleton, and these connections are involved in multiple functions such as nuclear positioning, shape and stiffness, cytoskeleton organization, mechanotransduction, gene expression, chromosome positioning, DNA repair, and cell migration.

Topics: Animals; Cell Nucleus; Cytoskeleton; Nuclear Envelope; Nuclear Proteins

PubMed: 28525760
DOI: 10.1016/j.cell.2017.05.014

Review

Authors: Matheus Fabiao de Lima, Mateus de Oliveira Lisboa, Lucas E L Terceiro...

Chromosomes are organized in distinct nuclear areas designated as chromosome territories (CT). The structural formation of CT is a consequence of chromatin packaging and organization that ultimately affects cell function. Chromosome positioning can identify structural signatures of genomic organization, especially for diseases where changes in gene expression contribute to a given phenotype. The study of CT in hematological diseases revealed chromosome position as an important factor for specific chromosome translocations. In this review, we highlight the history of CT theory, current knowledge on possible clinical applications of CT analysis, and the impact of CT in the development of hematological neoplasia such as multiple myeloma, leukemia, and lymphomas. Accumulating data on nuclear architecture in cancer allow one to propose the three-dimensional nuclear genomic landscape as a novel cancer biomarker for the future.

Topics: Cell Nucleus; Chromatin; Chromosomes; Genome; Hematologic Neoplasms; Humans

PubMed: 35456046
DOI: 10.3390/cells11081368

Review

Authors: John T Canty, Ruensern Tan, Emre Kusakci...

Dyneins make up a family of AAA+ motors that move toward the minus end of microtubules. Cytoplasmic dynein is responsible for transporting intracellular cargos in interphase cells and mediating spindle assembly and chromosome positioning during cell division. Other dynein isoforms transport cargos in cilia and power ciliary beating. Dyneins were the least studied of the cytoskeletal motors due to challenges in the reconstitution of active dynein complexes in vitro and the scarcity of high-resolution methods for in-depth structural and biophysical characterization of these motors. These challenges have been recently addressed, and there have been major advances in our understanding of the activation, mechanism, and regulation of dyneins. This review synthesizes the results of structural and biophysical studies for each class of dynein motors. We highlight several outstanding questions about the regulation of bidirectional transport along microtubules and the mechanisms that sustain self-coordinated oscillations within motile cilia.

Topics: Animals; Biological Transport; Cilia; Dyneins; Humans; Intracellular Space; Microtubules

PubMed: 33957056
DOI: 10.1146/annurev-biophys-111020-101511

Authors: Laia Vergés, Joan Blanco, Oliver Valero...

OBJECTIVE

To determine whether there is a preferential bivalent distribution pattern in metaphase I human spermatocytes and to analyze whether this positioning is influenced by chiasmata count, chromosome size, gene density, acrocentric morphology, and heterochromatic blocks.

DESIGN

Proximity frequencies of bivalents were evaluated with the analysis of meiotic preparations combining sequentially standard techniques and multiplex fluorescence in situ hybridization.

SETTING

University.

PATIENT(S)

Twenty-five men consulting for fertility problems.

INTERVENTION(S)

Unilateral testicular biopsies.

MAIN OUTCOME MEASURE(S)

Proximity analyses were performed for each bivalent considering as nearby bivalents those that were part of the first ring around the bivalent studied. Data were analyzed using Poisson regression models, multidimensional scaling, and cluster analysis.

RESULT(S)

Some bivalents have a preferential relative position. Significant associations among bivalents related to chromosome size, high gene density, and acrocentric morphology were observed. Chiasmata count and heterochromatic blocks were nonconditioning parameters of the bivalent organization.

CONCLUSION(S)

This study demonstrates that distribution in metaphase I is nonrandom and influenced by chromosome size, gene density, and acrocentric chromosome morphology. Results support that some features defining chromosome territories are maintained during meiosis.

Topics: Cell Size; Chromosome Structures; Chromosomes; Humans; Infertility, Male; Male; Metaphase; Spermatocytes

PubMed: 24355053
DOI: 10.1016/j.fertnstert.2013.11.013

Review

Authors: Andrew J Fritz, Nitasha Sehgal, Artem Pliss...

Spatial positioning is a fundamental principle governing nuclear processes. Chromatin is organized as a hierarchy from nucleosomes to Mbp chromatin domains (CD) or topologically associating domains (TADs) to higher level compartments culminating in chromosome territories (CT). Microscopic and sequencing techniques have substantiated chromatin organization as a critical factor regulating gene expression. For example, enhancers loop back to interact with their target genes almost exclusively within TADs, distally located coregulated genes reposition into common transcription factories upon activation, and Mbp CDs exhibit dynamic motion and configurational changes in vivo. A longstanding question in the nucleus field is whether an interactive nuclear matrix provides a direct link between structure and function. The findings of nonrandom radial positioning of CT within the nucleus suggest the possibility of preferential interaction patterns among populations of CT. Sequential labeling up to 10 CT followed by application of computer imaging and geometric graph mining algorithms revealed cell-type specific interchromosomal networks (ICN) of CT that are altered during the cell cycle, differentiation, and cancer progression. It is proposed that the ICN correlate with the global level of genome regulation. These approaches also demonstrated that the large scale 3-D topology of CT is specific for each CT. The cell-type specific proximity of certain chromosomal regions in normal cells may explain the propensity of distinct translocations in cancer subtypes. Understanding how genes are dysregulated upon disruption of the normal "wiring" of the nucleus by translocations, deletions, and amplifications that are hallmarks of cancer, should enable more targeted therapeutic strategies.

Topics: Animals; Cell Nucleus; Chromatin; Chromosomes; Gene Expression Regulation; Genome; Humans

PubMed: 30664301
DOI: 10.1002/gcc.22732

Review

Authors: K V S K Arjun Chowdary, Ramswaroop Saini, Amit Kumar Singh...

Meiosis is a distinctive type of cell division that reorganizes genetic material between generations. The initial stages of meiosis consist of several crucial steps which include double strand break, homologous chromosome pairing, break repair and crossover. Crossover frequency varies depending on the position on the chromosome, higher at euchromatin region and rare at heterochromatin, centromeres, telomeres and ribosomal DNA. Crossover positioning is dependent on various factors, especially epigenetic modifications. DNA methylation, histone post-translational modifications, histone variants and non-coding RNAs are most probably playing an important role in positioning of crossovers on a chromosomal level as well as hotspot level. DNA methylation negatively regulates crossover frequency and its effect is visible in centromeres, pericentromeres and heterochromatin regions. Pericentromeric chromatin and heterochromatin mark studies have been a centre of attraction in meiosis. Crossover hotspots are associated with euchromatin regions having specific chromatin modifications such as H3K4me3, H2A.Z. and H3 acetylation. This review will provide the current understanding of the epigenetic role in plants during meiotic recombination, chromosome synapsis, double strand break and hotspots with special attention to euchromatin and heterochromatin marks. Further, the role of epigenetic modifications in regulating meiosis and crossover in other organisms is also discussed.

PubMed: 38222277
DOI: 10.1007/s12298-023-01390-w

Review

Authors: Sigal Shachar, Tom Misteli

The eukaryotic genome is organized in a manner that allows folding of the genetic material in the confined space of the cell nucleus, while at the same time enabling its physiological function. A major principle of spatial genome organization is the non-random position of genomic loci relative to other loci and to nuclear bodies. The mechanisms that determine the spatial position of a locus, and how position affects function, are just beginning to be characterized. Initial results suggest that there are multiple, gene-specific mechanisms and the involvement of a wide range of cellular machineries. In this Commentary, we review recent findings from candidate approaches and unbiased screening methods that provide initial insight into the cellular mechanisms of positioning and their functional consequences. We highlight several specific mechanisms, including tethering of genome regions to the nuclear periphery, passage through S-phase and histone modifications, that contribute to gene positioning in yeast, plants and mammals.

Topics: Animals; Cell Nucleus; Chromosome Positioning; DNA Replication; Genome; Humans; Models, Biological

PubMed: 28404786
DOI: 10.1242/jcs.199786