scholarly journals Meiotic Double-Strand Break Processing and Crossover Patterning Are Regulated in a Sex-Specific Manner by BRCA1–BARD1 in Caenorhabditis elegans

Genetics ◽  
2020 ◽  
Vol 216 (2) ◽  
pp. 359-379 ◽  
Author(s):  
Qianyan Li ◽  
Sara Hariri ◽  
JoAnne Engebrecht
Keyword(s):  
Caenorhabditis Elegans ◽  
Meiotic Recombination ◽  
Sex Chromosome ◽  
Strand Break ◽  
Male Meiosis ◽  
Female Meiosis ◽  
Link Type ◽  
Meiotic Sex Chromosome Inactivation ◽  
Specific Manner ◽  
Dna End Resection

Meiosis is regulated in a sex-specific manner to produce two distinct gametes, sperm and oocytes, for sexual reproduction. To determine how meiotic recombination is regulated in spermatogenesis, we analyzed the meiotic phenotypes of mutants in the tumor suppressor E3 ubiquitin ligase BRC-1-BRD-1 complex in Caenorhabditis elegans male meiosis. Unlike in mammals, this complex is not required for meiotic sex chromosome inactivation, the process whereby hemizygous sex chromosomes are transcriptionally silenced. Interestingly, brc-1 and brd-1 mutants show meiotic recombination phenotypes that are largely opposing to those previously reported for female meiosis. Fewer meiotic recombination intermediates marked by the recombinase RAD-51 were observed in brc-1 and brd-1 mutants, and the reduction in RAD-51 foci could be suppressed by mutation of nonhomologous-end-joining proteins. Analysis of GFP::RPA-1 revealed fewer foci in the brc-1brd-1 mutant and concentration of BRC-1-BRD-1 to sites of meiotic recombination was dependent on DNA end resection, suggesting that the complex regulates the processing of meiotic double-strand breaks to promote repair by homologous recombination. Further, BRC-1-BRD-1 is important to promote progeny viability when male meiosis is perturbed by mutations that block the pairing and synapsis of different chromosome pairs, although the complex is not required to stabilize the RAD-51 filament as in female meiosis under the same conditions. Analyses of crossover designation and formation revealed that BRC-1-BRD-1 inhibits supernumerary COs when meiosis is perturbed. Together, our findings suggest that BRC-1-BRD-1 regulates different aspects of meiotic recombination in male and female meiosis.

scholarly journals C. elegans BRC-1-BRD-1 functions at an early step of DSB processing and inhibits supernumerary crossovers during male meiosis

2020 ◽  
Author(s):  
Qianyan Li ◽  
Sara Hariri ◽  
JoAnne Engebrecht
Keyword(s):  
Meiotic Recombination ◽  
Sex Chromosome ◽  
Male Meiosis ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Female Meiosis ◽  
Strand Breaks ◽  
C Elegans ◽  
Meiotic Sex Chromosome Inactivation ◽  
Dna End Resection

AbstractMeiosis is regulated in a sex-specific manner to produce two distinct gametes, sperm and oocytes, for sexual reproduction. To determine how meiotic recombination is regulated in spermatogenesis, we analyzed the meiotic phenotypes of mutants in the tumor suppressor E3 ubiquitin ligase BRC-1-BRD-1 complex in Caenorhabditis elegans male meiosis. Unlike in mammals, this complex is not required for meiotic sex chromosome inactivation, the process whereby hemizygous sex chromosomes are transcriptionally silenced. Interestingly, brc-1 and brd-1 mutants showed meiotic recombination phenotypes that are largely opposing to those previously reported for female meiosis. Fewer meiotic recombination foci marked by the recombinase RAD-51 were observed in brc-1 and brd-1 mutants, and the reduction in RAD-51 foci can be suppressed by mutation of nonhomologous end joining proteins. We show that concentration of BRC-1-BRD-1 to sites of meiotic recombination is dependent on DNA end resection, suggesting that BRC-1-BRD-1 regulates the processing of meiotic double strand breaks to promote repair by homologous recombination, similar to a role for the complex in somatic cells. We also show that BRC-1-BRD-1 is important to promote progeny viability when male meiosis is perturbed by mutations that block the pairing and synapsis of different chromosome pairs, although the complex is not required to stabilize the RAD-51 filament as in female meiosis under the same conditions. Analyses of crossover designation and formation reveal that BRC-1-BRD-1 inhibits supernumerary crossovers when meiosis is perturbed. Together, our findings suggest that BRC-1-BRD-1 regulates different aspects of meiotic recombination in male and female meiosis.

scholarly journals Chromosome Integrity is Required for the Initiation of Meiotic Sex Chromosome Inactivation in Caenorhabditis elegans

2020 ◽  
Author(s):  
Yisrael Rappaport ◽  
Hanna Achache ◽  
Roni Falk ◽  
Omer Murik ◽  
Oren Ram ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Chromosome Inactivation ◽  
Chromatin Modifications ◽  
Meiotic Sex Chromosome Inactivation ◽  
Chromosome Integrity ◽  
Sex Chromosome Inactivation

During meiosis of heterogametic cells, such as XY meiocytes, sex chromosomes of many species undergo transcriptional silencing known as meiotic sex chromosome inactivation (MSCI). Silencing also occurs in aberrantly unsynapsed autosomal chromatin. The silencing of unsynapsed chromatin, is assumed to be the underline mechanism for MSCI. Initiation of MSCI is disrupted in meiocytes with sex chromosome-autosome translocations. Whether this is due to aberrant synapsis or the lack of sex chromosome integrity has never been determined. To address this, we used CRISPR to engineer Caenorhabditis elegans stable strains with broken X chromosomes that didn’t undergo translocations with autosomes. In early meiotic nuclei of these mutants, the X fragments lack silent chromatin modifications and instead the fragments are enriched with transcribing chromatin modifications. Moreover, the level of active RNA polymerase II staining on the X fragments in mutant nuclei is similar to that on autosomes, indicating active transcription on the X. Contrary to previous models, which predicted that any unsynapsed chromatin is silenced during meiosis, X fragments that did not synapse were robustly stained with RNA polymerase II and gene expression levels were high throughout the broken X. Therefore, lack of synapsis does not trigger MSCI if sex chromosome integrity is lost. Moreover, our results suggest that a unique character of the chromatin of sex chromosomes underlies their lack of meiotic silencing due to both unsynapsed chromatin and sex chromosome mechanisms when their integrity is lost.

scholarly journals Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis

2008 ◽  
Vol 180 (4) ◽  
pp. 673-679 ◽  
Author(s):  
Fang Yang ◽  
Sigrid Eckardt ◽  
N. Adrian Leu ◽  
K. John McLaughlin ◽  
Peijing Jeremy Wang
Keyword(s):  
Meiotic Recombination ◽  
Strand Break ◽  
Male Meiosis ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Recombination Proteins ◽  
Meiotic Chromosomes ◽  
Dna Double Strand Break

During meiosis, homologous chromosomes undergo synapsis and recombination. We identify TEX15 as a novel protein that is required for chromosomal synapsis and meiotic recombination. Loss of TEX15 function in mice causes early meiotic arrest in males but not in females. Specifically, TEX15-deficient spermatocytes exhibit a failure in chromosomal synapsis. In mutant spermatocytes, DNA double-strand breaks (DSBs) are formed, but localization of the recombination proteins RAD51 and DMC1 to meiotic chromosomes is severely impaired. Based on these data, we propose that TEX15 regulates the loading of DNA repair proteins onto sites of DSBs and, thus, its absence causes a failure in meiotic recombination.

scholarly journals Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation

2008 ◽  
Vol 182 (2) ◽  
pp. 263-276 ◽  
Author(s):  
Shantha K. Mahadevaiah ◽  
Déborah Bourc'his ◽  
Dirk G. de Rooij ◽  
Timothy H. Bestor ◽  
James M.A. Turner ◽  
...  
Keyword(s):  
Sex Chromosome ◽  
Male Meiosis ◽  
Chromosome Inactivation ◽  
Null Mouse ◽  
Dna Double Strand Breaks ◽  
Meiotic Silencing ◽  
Meiotic Sex Chromosome Inactivation ◽  
Y Chromosomes ◽  
Meiotic Dsbs ◽  
Sex Chromosome Inactivation

Chromosome synapsis during zygotene is a prerequisite for the timely homologous recombinational repair of meiotic DNA double-strand breaks (DSBs). Unrepaired DSBs are thought to trigger apoptosis during midpachytene of male meiosis if synapsis fails. An early pachytene response to asynapsis is meiotic silencing of unsynapsed chromatin (MSUC), which, in normal males, silences the X and Y chromosomes (meiotic sex chromosome inactivation [MSCI]). In this study, we show that MSUC occurs in Spo11-null mouse spermatocytes with extensive asynapsis but lacking meiotic DSBs. In contrast, three mutants (Dnmt3l, Msh5, and Dmc1) with high levels of asynapsis and numerous persistent unrepaired DSBs have a severely impaired MSUC response. We suggest that MSUC-related proteins, including the MSUC initiator BRCA1, are sequestered at unrepaired DSBs. All four mutants fail to silence the X and Y chromosomes (MSCI failure), which is sufficient to explain the midpachytene apoptosis. Apoptosis does not occur in mice with a single additional asynapsed chromosome with unrepaired meiotic DSBs and no disturbance of MSCI.

scholarly journals Epigenetic regulation in male germ cells

Reproduction ◽  
2008 ◽  
Vol 136 (2) ◽  
pp. 131-146 ◽  
Author(s):  
Natasha M Zamudio ◽  
Suyinn Chong ◽  
Moira K O'Bryan
Keyword(s):  
Germ Cells ◽  
Epigenetic Regulation ◽  
Sex Chromosome ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Male Meiosis ◽  
Paternal Effects ◽  
Male Germ Cells ◽  
Epigenetic Effects ◽  
Meiotic Sex Chromosome Inactivation

In recent years, it has become increasingly clear that epigenetic regulation of gene expression is critical during spermatogenesis. In this review, the epigenetic regulation and the consequences of its aberrant regulation during mitosis, meiosis and spermiogenesis are described. The current knowledge on epigenetic modifications that occur during male meiosis is discussed, with special attention on events that define meiotic sex chromosome inactivation. Finally, the recent studies focused on transgenerational and paternal effects in mice and humans are discussed. In many cases, these epigenetic effects resulted in impaired fertility and potentially long-ranging affects underlining the importance of research in this area.

scholarly journals γ-H2AX is present at mouse meiotic kinetochores

2020 ◽  
Author(s):  
Andrea Guajardo ◽  
Alberto Viera ◽  
María Teresa Parra ◽  
Manuel M. Valdivia ◽  
Julio S. Rufas ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Meiotic Prophase ◽  
Male Mouse ◽  
Sex Chromosome ◽  
Double Strand Breaks ◽  
Chromosome Inactivation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Meiotic Sex Chromosome Inactivation ◽  
First Time

AbstractThe histone variant H2AX phosphorylated on serine 139, named γ-H2AX, is a canonical DNA double-strand breaks marker. During mammalian meiotic prophase I, γ-H2AX participates in meiotic recombination, meiotic sex chromosome inactivation and meiotic silencing of unsynapsed chromatin. In this study, we have analyzed the distribution of γ-H2AX during male mouse meiosis by immunofluorescence on spread and squashed spermatocytes. We have found that γ-H2AX locates at the inner kinetochore plate of meiotic kinetochores in both meiotic divisions. Therefore our results, for the first time, uncover a novel role for γ-H2AX at mammalian meiotic kinetochores.

scholarly journals Multiple 9-1-1 complexes promote homolog synapsis, DSB repair, and ATR signaling during mammalian meiosis

2021 ◽  
Author(s):  
Catalina Pereira ◽  
Gerardo A Arroyo-Martinez ◽  
Matthew Z Guo ◽  
Emma R Kelly ◽  
Kathryn J Grive ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Sex Chromosome ◽  
Strand Break ◽  
Dsb Repair ◽  
Meiotic Chromosomes ◽  
Gamete Formation ◽  
Meiotic Sex Chromosome Inactivation ◽  
Damage Response ◽  
Synaptonemal Complex Formation ◽  
Atr Activation

DNA damage response mechanisms have meiotic roles that ensure successful gamete formation. While completion of meiotic double-strand break (DSB) repair requires the canonical RAD9A-RAD1-HUS1 (9A-1-1) complex, mammalian meiocytes also express RAD9A and HUS1 paralogs, RAD9B and HUS1B, predicted to form alternative 9-1-1 complexes. The RAD1 subunit is shared by all predicted 9-1-1 complexes and localizes to meiotic chromosomes even in the absence of HUS1 and RAD9A. Here we report that testis-specific RAD1 disruption resulted in impaired DSB repair, germ cell depletion and infertility. Unlike Hus1 or Rad9a disruption, Rad1 loss also caused defects in homolog synapsis, ATR signaling and meiotic sex chromosome inactivation. Comprehensive testis phosphoproteomics revealed that RAD1 and ATR coordinately regulate numerous proteins involved in DSB repair, meiotic silencing, synaptonemal complex formation, and cohesion. Together, these results establish critical roles for both canonical and alternative 9-1-1 complexes in meiotic ATR activation and successful prophase I completion.

scholarly journals Epigenetic Dysregulation of Mammalian Male Meiosis Caused by Interference of Recombination and Synapsis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2311
Author(s):  
Roberto de la Fuente ◽  
Florencia Pratto ◽  
Abrahan Hernández-Hernández ◽  
Marcia Manterola ◽  
Pablo López-Jiménez ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Male Meiosis ◽  
Epigenetic Marks ◽  
Prophase I ◽  
Recombination Proteins ◽  
Meiotic Sex Chromosome Inactivation ◽  
Y Chromosomes ◽  
Genes Encoding

Meiosis involves a series of specific chromosome events, namely homologous synapsis, recombination, and segregation. Disruption of either recombination or synapsis in mammals results in the interruption of meiosis progression during the first meiotic prophase. This is usually accompanied by a defective transcriptional inactivation of the X and Y chromosomes, which triggers a meiosis breakdown in many mutant models. However, epigenetic changes and transcriptional regulation are also expected to affect autosomes. In this work, we studied the dynamics of epigenetic markers related to chromatin silencing, transcriptional regulation, and meiotic sex chromosome inactivation throughout meiosis in knockout mice for genes encoding for recombination proteins SPO11, DMC1, HOP2 and MLH1, and the synaptonemal complex proteins SYCP1 and SYCP3. These models are defective in recombination and/or synapsis and promote apoptosis at different stages of progression. Our results indicate that impairment of recombination and synapsis alter the dynamics and localization pattern of epigenetic marks, as well as the transcriptional regulation of both autosomes and sex chromosomes throughout prophase-I progression. We also observed that the morphological progression of spermatocytes throughout meiosis and the dynamics of epigenetic marks are processes that can be desynchronized upon synapsis or recombination alteration. Moreover, we detected an overlap of early and late epigenetic signatures in most mutants, indicating that the normal epigenetic transitions are disrupted. This can alter the transcriptional shift that occurs in spermatocytes in mid prophase-I and suggest that the epigenetic regulation of sex chromosomes, but also of autosomes, is an important factor in the impairment of meiosis progression in mammals.

scholarly journals Transcriptomics of Meiosis in the Male Mouse

2021 ◽  
Vol 9 ◽  
Author(s):  
Adriana Geisinger ◽  
Rosana Rodríguez-Casuriaga ◽  
Ricardo Benavente
Keyword(s):  
Sex Chromosome ◽  
Expression Patterns ◽  
Male Meiosis ◽  
Practical Reasons ◽  
Isolated Cells ◽  
Meiotic Sex Chromosome Inactivation ◽  
Technical Advances ◽  
Non Coding Rnas ◽  
Flow Cytometry Sorting

Molecular studies of meiosis in mammals have been long relegated due to some intrinsic obstacles, namely the impossibility to reproduce the process in vitro, and the difficulty to obtain highly pure isolated cells of the different meiotic stages. In the recent years, some technical advances, from the improvement of flow cytometry sorting protocols to single-cell RNAseq, are enabling to profile the transcriptome and its fluctuations along the meiotic process. In this mini-review we will outline the diverse methodological approaches that have been employed, and some of the main findings that have started to arise from these studies. As for practical reasons most studies have been carried out in males, and mostly using mouse as a model, our focus will be on murine male meiosis, although also including specific comments about humans. Particularly, we will center on the controversy about gene expression during early meiotic prophase; the widespread existing gap between transcription and translation in meiotic cells; the expression patterns and potential roles of meiotic long non-coding RNAs; and the visualization of meiotic sex chromosome inactivation from the RNAseq perspective.

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