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Developmental Cell Dec 2023During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the...
During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the chromatin remodeling in oogenesis and characteristics of homologous pairing remain largely elusive. We comprehensively compared chromatin structures and transcriptomes at successive substages of meiotic prophase in both female and male mice using low-input high-through chromosome conformation capture (Hi-C) and RNA sequencing (RNA-seq). Compartments and topologically associating domains (TADs) gradually disappeared and slowly recovered in both sexes. We found that homologs adopted different sex-conserved pairing strategies prior to and after the leptotene-to-zygotene transition, changing from long interspersed nuclear element (LINE)-enriched compartments B to short interspersed nuclear element (SINE)-enriched compartments A. We complemented marker genes and predicted the sex-specific meiotic sterile genes for each substage. This study provides valuable insights into the similarities and distinctions between sexes in chromosome architecture, homologous pairing, and transcriptome during meiotic prophase of both oogenesis and spermatogenesis.
Topics: Male; Female; Mice; Animals; Meiosis; Spermatogenesis; Prophase; Meiotic Prophase I; Chromatin; Oogenesis; Chromosome Pairing
PubMed: 37963468
DOI: 10.1016/j.devcel.2023.10.009 -
Cells Jun 2023The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC... (Review)
Review
The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC mediates the synapses of the homologous chromosomes, leading to the formation of bivalents, and physically supports the formation of programmed double-strand breaks (DSBs) and their subsequent repair and maturation into crossovers (COs), which are essential for genome haploidization. Defects in the assembly of the SC or in the function of the associated meiotic recombination machinery can lead to meiotic arrest and human infertility. The majority of proteins and complexes involved in these processes are exclusively expressed during meiosis or harbor meiosis-specific subunits, although some have dual functions in somatic DNA repair and meiosis. Consistent with their functions, aberrant expression and malfunctioning of these genes have been associated with cancer development. In this review, we focus on the significance of the SC and their meiotic-associated proteins in human fertility, as well as how human genetic variants encoding for these proteins affect the meiotic process and contribute to infertility and cancer development.
Topics: Synaptonemal Complex; Humans; Meiosis; Neoplasms; Infertility; Male; Female; Recombination, Genetic
PubMed: 37443752
DOI: 10.3390/cells12131718 -
Philosophical Transactions. Series A,... Jun 2021We report that high-density single-molecule super-resolution microscopy can be achieved with a conventional epifluorescence microscope set-up and a mercury arc lamp. The...
We report that high-density single-molecule super-resolution microscopy can be achieved with a conventional epifluorescence microscope set-up and a mercury arc lamp. The configuration termed as laser-free super-resolution microscopy (LFSM) is an extension of single-molecule localization microscopy (SMLM) techniques and allows single molecules to be switched on and off (a phenomenon termed as 'blinking'), detected and localized. The use of a short burst of deep blue excitation (350-380 nm) can be further used to reactivate the blinking, once the blinking process has slowed or stopped. A resolution of 90 nm is achieved on test specimens (mouse and amphibian meiotic chromosomes). Finally, we demonstrate that stimulated emission depletion and LFSM can be performed on the same biological sample using a simple commercial mounting medium. It is hoped that this type of correlative imaging will provide a basis for a further enhanced resolution. This article is part of the Theo Murphy meeting issue 'Super-resolution structured illumination microscopy (part 1)'.
Topics: Amphibians; Animals; Chromosomes; Equipment Design; Fluorescent Dyes; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Organic Chemicals; Proof of Concept Study; Single Molecule Imaging; Synaptonemal Complex; Xanthenes
PubMed: 33896204
DOI: 10.1098/rsta.2020.0144 -
Annual Review of Genetics Nov 2021The specialized two-stage meiotic cell division program halves a cell's chromosome complement in preparation for sexual reproduction. This reduction in ploidy requires... (Review)
Review
The specialized two-stage meiotic cell division program halves a cell's chromosome complement in preparation for sexual reproduction. This reduction in ploidy requires that in meiotic prophase, each pair of homologous chromosomes (homologs) identify one another and form physical links through DNA recombination. Here, we review recent advances in understanding the complex morphological changes that chromosomes undergo during meiotic prophase to promote homolog identification and crossing over. We focus on the structural maintenance of chromosomes (SMC) family cohesin complexes and the meiotic chromosome axis, which together organize chromosomes and promote recombination. We then discuss the architecture and dynamics of the conserved synaptonemal complex (SC), which assembles between homologs and mediates local and global feedback to ensure high fidelity in meiotic recombination. Finally, we discuss exciting new advances, including mechanisms for boosting recombination on particular chromosomes or chromosomal domains and the implications of a new liquid crystal model for SC assembly and structure.
Topics: Chromosome Pairing; Chromosomes; Homologous Recombination; Meiosis; Synaptonemal Complex
PubMed: 34530636
DOI: 10.1146/annurev-genet-071719-020235 -
Nucleus (Austin, Tex.) Dec 2024Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing... (Review)
Review
Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I.
Topics: Heterochromatin; Centromere; Meiosis; Chromosome Pairing
PubMed: 38488152
DOI: 10.1080/19491034.2024.2328719 -
Clinical and Translational Medicine Jul 2022An impeccable female meiotic prophase is critical for producing a high-quality oocyte and, ultimately, a healthy newborn. SYCP3 is a key component of the synaptonemal...
BACKGROUND
An impeccable female meiotic prophase is critical for producing a high-quality oocyte and, ultimately, a healthy newborn. SYCP3 is a key component of the synaptonemal complex regulating meiotic homologous recombination. However, what regulates SYCP3 stability is unknown.
METHODS
Fertility assays, follicle counting, meiotic prophase stage (leptotene, zygotene, pachytene and diplotene) analysis and live imaging were employed to examine how FBXW24 knockout (KO) affect female fertility, follicle reserve, oocyte quality, meiotic prophase progression of female germ cells, and meiosis of oocytes. Western blot and immunostaining were used to examined the levels & signals (intensity, foci) of SYCP3 and multiple key DSB indicators & repair proteins (γH2AX, RPA2, p-CHK2, RAD51, MLH1, HORMAD1, TRIP13) after FBXW24 KO. Co-IP and immuno-EM were used to examined the interaction between FBXW24 and SYCP3; Mass spec was used to characterize the ubiquitination sites in SYCP3; In vivo & in vitro ubiquitination assays were utilized to determine the key sites in SYCP3 & FBXW24 for ubiquitination.
RESULTS
Fbxw24-knockout (KO) female mice were infertile due to massive oocyte death upon meiosis entry. Fbxw24-KO oocytes were defective due to elevated DNA double-strand breaks (DSBs) and inseparable homologous chromosomes. Fbxw24-KO germ cells showed increased SYCP3 levels, delayed prophase progression, increased DSBs, and decreased crossover foci. Next, we found that FBXW24 directly binds and ubiquitinates SYCP3 to regulate its stability. In addition, several key residues important for SYCP3 ubiquitination and FBXW24 ubiquitinating activity were characterized.
CONCLUSIONS
We proposed that FBXW24 regulates the timely degradation of SYCP3 to ensure normal crossover and DSB repair during pachytene. FBXW24-KO delayed SYCP3 degradation and DSB repair from pachytene until metaphase II (MII), ultimately causing failure in oocyte maturation, oocyte death, and infertility.
Topics: Animals; Cell Cycle Proteins; DNA-Binding Proteins; F-Box Proteins; Female; Meiosis; Mice; Prophase; Synaptonemal Complex; Ubiquitination
PubMed: 35858239
DOI: 10.1002/ctm2.891 -
Current Opinion in Plant Biology Oct 2019Meiotic recombination provides genetic diversity in populations and ensures accurate homologous chromosome segregation for genome integrity. During meiosis,... (Review)
Review
Meiotic recombination provides genetic diversity in populations and ensures accurate homologous chromosome segregation for genome integrity. During meiosis, recombination processes, from DNA double strand breaks (DSBs) to crossover formation are tightly linked to higher order chromosome structure, including chromatid cohesion, axial element formation, homolog pairing and synapsis. The extensive studies on plant meiosis have revealed the important conserved roles for meiotic proteins in homologous recombination. Recent works have focused on elucidating the mechanistic basis of how meiotic proteins regulate recombination events via protein complex formation and modifications such as phosphorylation, ubiquitination, and SUMOylation. Here, we highlight recent advances on the signaling and modifications of meiotic proteins that mediate the formation of DSBs and crossovers in plants.
Topics: Chromosome Pairing; DNA Breaks, Double-Stranded; DNA Repair; Homologous Recombination; Meiosis
PubMed: 31048232
DOI: 10.1016/j.pbi.2019.04.001 -
Annual Review of Genomics and Human... Aug 2023In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome... (Review)
Review
In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome axes. The mammalian SC comprises at least eight largely coiled-coil proteins that interact and self-assemble to generate a long, zipper-like structure that holds homologous chromosomes in close proximity and promotes the formation of genetic crossovers and accurate meiotic chromosome segregation. In recent years, numerous mutations in human SC genes have been associated with different types of male and female infertility. Here, we integrate structural information on the human SC with mouse and human genetics to describe the molecular mechanisms by which SC mutations can result in human infertility. We outline certain themes in which different SC proteins are susceptible to different types of disease mutation and how genetic variants with seemingly minor effects on SC proteins may act as dominant-negative mutations in which the heterozygous state is pathogenic.
Topics: Male; Female; Humans; Mice; Animals; Synaptonemal Complex; Chromosome Pairing; Meiosis; Infertility; Mutation; Mammals
PubMed: 37159901
DOI: 10.1146/annurev-genom-110122-090239 -
Molecular Aspects of Medicine Jun 2024Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic... (Review)
Review
Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic prophase is characterized by the meiosis-specific chromosomal events such as chromosome recombination and homolog synapsis. Meiosis initiator (MEIOSIN) and stimulated by retinoic acid gene 8 (STRA8) initiate meiosis by activating the meiotic genes by installing the meiotic prophase program at pre-meiotic S phase. This review highlights the mechanisms of meiotic initiation and meiotic prophase progression from the point of the gene expression program and its relevance to infertility. Furthermore, upstream pathways that regulate meiotic initiation will be discussed in the context of spermatogenic development, indicating the sexual differences in the mode of meiotic entry.
Topics: Spermatogenesis; Humans; Meiosis; Animals; Male; Meiotic Prophase I; Prophase
PubMed: 38797021
DOI: 10.1016/j.mam.2024.101282 -
Nature Structural & Molecular Biology Apr 2023Cohesins are ancient and ubiquitous regulators of chromosome architecture and function, but their diverse roles and regulation remain poorly understood. During meiosis,...
Cohesins are ancient and ubiquitous regulators of chromosome architecture and function, but their diverse roles and regulation remain poorly understood. During meiosis, chromosomes are reorganized as linear arrays of chromatin loops around a cohesin axis. This unique organization underlies homolog pairing, synapsis, double-stranded break induction, and recombination. We report that axis assembly in Caenorhabditis elegans is promoted by DNA-damage response (DDR) kinases that are activated at meiotic entry, even in the absence of DNA breaks. Downregulation of the cohesin-destabilizing factor WAPL-1 by ATM-1 promotes axis association of cohesins containing the meiotic kleisins COH-3 and COH-4. ECO-1 and PDS-5 also contribute to stabilizing axis-associated meiotic cohesins. Further, our data suggest that cohesin-enriched domains that promote DNA repair in mammalian cells also depend on WAPL inhibition by ATM. Thus, DDR and Wapl seem to play conserved roles in cohesin regulation in meiotic prophase and proliferating cells.
Topics: Animals; Meiosis; Chromosomal Proteins, Non-Histone; Chromosomes; Cell Cycle Proteins; Chromosome Pairing; Caenorhabditis elegans; Mammals; Cohesins
PubMed: 36879153
DOI: 10.1038/s41594-023-00929-5