Dosage Compensation of an Aneuploid Genome in Mouse Spermatogenic Cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE54683 | GEO | 2016/03/30
SECONDARY ACCESSION(S): PRJNA237357
REPOSITORIES: GEO
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Project description:Autosomal trisomies and monosomies bring serious threats to embryonic development through transcriptional disarray primarily caused by the dosage effect of the aneuploid part of the genome. The present study compared the effect of a mouse viable 30 Mb segmental trisomy on the genome-wide transcriptional profile of somatic (liver) cells and male germ cells. While the 1.6-fold change in expression of triplicated genes reflected the gene dosage in liver cells, the extra copy was almost fully compensated in early pachytene spermatocytes, showing 1.18-fold increase. Allele-specific semi-quantitative evaluation of steady-state mRNA levels of the triplicated Amdhd2 gene revealed silencing evenly distributed among all three copies in these meiotic cells. Although more pronounced, the dosage compensation of trisomic genes was concordant with the incidence of HORMAD2 and γH2AX markers of unsynapsed chromatin. The possible explanations include insufficient sensitivity to detect both MSUC markers in the 30 Mb region of the chromosome, or an early silencing effect of another epigenetic factor. Taken together, our results indicate that the meiotic silencing of unsynapsed chromatin is the major but not the only factor driving the dosage compensation of triplicated genes in primary spermatocytes. We compared the global expression profiles in isolated popoulations of meiotic cells and liver cells of Ts43H trisomic males and their t121/D17 euploid siblings.
2016-03-30 | E-GEOD-54683 | biostudies-arrayexpress
Project description:Ubiquitylation of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitylation, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. Here we show that the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates, in combination with the ubiquitin-conjugating enzyme HR6B, the ubiquitination of histone H2A. UBR2 interacts with HR6B and H2A and promotes the HR6B-H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. We propose a model, in which UBR2 on axial elements of the X-Y pair enables HR6B on the linked chromatin domain to repeat histone ubiquitination cycles while scanning a string of nucleosomes. Our results suggest that histone ubiquitination in germ cells may be mediated by E3-E2 pairs distinct from those in somatic cells, providing a new insight into chromatin remodeling and gene expression regulation. For each genotype, 2 testes were collected from different individual in same litter at 17 days old. Biotinylated cRNA was produced and hybridized on Affimetrix mouse genome 430A 2.0 array.
2010-03-03 | E-GEOD-18824 | biostudies-arrayexpress
Project description:Ubiquitylation of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitylation, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. Here we show that the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates, in combination with the ubiquitin-conjugating enzyme HR6B, the ubiquitination of histone H2A. UBR2 interacts with HR6B and H2A and promotes the HR6B-H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. We propose a model, in which UBR2 on axial elements of the X-Y pair enables HR6B on the linked chromatin domain to repeat histone ubiquitination cycles while scanning a string of nucleosomes. Our results suggest that histone ubiquitination in germ cells may be mediated by E3-E2 pairs distinct from those in somatic cells, providing a new insight into chromatin remodeling and gene expression regulation.
2009-12-31 | GSE18824 | GEO
Project description:In mammals and several other taxa, the ability of males to cope with the limited synapsis of the X and Y chromosomes during prophase I of meiosis relies on the process of meiotic sex chromosome inactivation (MSCI). Components of the somatic DNA damage response machinery, including ATR, TOPBP1, MDC1 and BRCA1 play key roles in MSCI, although how they establish XY silencing remains incompletely understood. In particular, it remains unclear how DDR factors coordinate XY silencing with DNA repair, chromosome synapsis and the formation of the sex body, a distinct phase-separated sub-nuclear structure formed during prophase I to house the unsynapsed XY bivalent. Here we report a mutant mouse (Topbp1B5/B5), harboring mutations in the BRCT5 domain of Topbp1, that shows impaired XY silencing but grossly normal sex body formation. While Topbp1B5/B5 mice are viable, without detectable somatic defects, males are completely infertile. Distinct from mice lacking ATR or TOPBP1 specifically during meiosis, Topbp1B5/B5 males exhibit normal chromosome synapsis and canonical markers of DNA repair in early prophase I. ATR signaling is mostly intact in Topbp1B5/B5 spermatocytes, although specific ATR-dependent events are disrupted, including localization of the RNA:DNA helicase Senataxin to chromatin loops of the XY. Strikingly, while Topbp1B5/B5 spermatocytes are able to initiate MSCI the completion of gene silencing is defective, with a subset of X chromosome genes displaying distinct patterns of transcriptional deregulation. These findings suggest a non-canonical role for the ATR-TOPBP1 signaling axis in XY silencing dynamics at advanced stages in pachynema. This is the first DDR mutant that separates XY silencing from sex body formation, as well as TOPBP1’s role in spermatogenesis from its roles in organismal viability.
2024-02-09 | PXD042199 | Pride
Project description:Balanced constitutional reciprocal translocations are the most common structural chromosomal rearrangements identified in man and pigs. Carriers are generally phenotypically normal, but such rearrangements frequently lead to reproductive disorders. In reciprocal translocation heterozygotes, the homologous regions of the normal and derivative chromosomes involved in the rearrangement pair during the prophase of the first meiotic division, thanks to the synaptonemal complex (SC), and form a particular structure called quadrivalent. In some cases, chromosomal regions (within the quadrivalent) remain unsynapsed, especially around the breakpoints, which may trigger meiosis checkpoints leading to spermatogenesis arrest at the pachytene stage. Several hypotheses have been proposed to explain such effects of pairing failure on gametogenesis. The first one is an altered transcription of the genes located on the unpaired segments. Indeed, studies conducted in mice revealed a transcriptional repression of unpaired regions by a specific mechanism called “Meiotic Silencing of Unsynapsed Chromatin” (MSUC) in individuals with a partial or total spermatogenesis arrest (Turner et al., 2005). If some genes necessary for the proper course of meiosis are located in such unsynapsed genomic regions, MSUC may result in an arrest of the meiotic division. Secondly, associations between the “quadrivalent” and the XY bivalent which is transcriptionally silenced by a phenomenon known as meiotic sex chromosome inactivation (MSCI, (Turner, 2007) were also observed in individuals with altered semen parameters (azoospermic or oligospemic) (Oliver-Bonet et al., 2005; Sciurano et al., 2007a, 2012). Such an association could result in a partial reactivation of the XY body (XYB) leading to the expression of some genes located on the X chromosome (Lifschytz and Lindsley, 1972), or result in the spreading of the XYB inactivation towards the autosomal segments attached to the XYB, without reactivation of the latter (Jaafar et al., 1993). Beyond the potential spermatogenesis failure mentioned above, reciprocal translocations are systematically responsible for the production of genetically unbalanced gametes. Here we report the detailed analysis of the whole meiotic process (from spermatocytes to spermatozoa) in the case of a constitutional balanced reciprocal translocation responsible for severe oligoasthenoteratospermia.
2016-06-30 | GSE80693 | GEO
Project description:Balanced constitutional reciprocal translocations are the most common structural chromosomal rearrangements identiï¬ed in man and pigs. Carriers are generally phenotypically normal, but such rearrangements frequently lead to reproductive disorders. In reciprocal translocation heterozygotes, the homologous regions of the normal and derivative chromosomes involved in the rearrangement pair during the prophase of the first meiotic division, thanks to the synaptonemal complex (SC), and form a particular structure called quadrivalent. In some cases, chromosomal regions (within the quadrivalent) remain unsynapsed, especially around the breakpoints, which may trigger meiosis checkpoints leading to spermatogenesis arrest at the pachytene stage. Several hypotheses have been proposed to explain such effects of pairing failure on gametogenesis. The first one is an altered transcription of the genes located on the unpaired segments. Indeed, studies conducted in mice revealed a transcriptional repression of unpaired regions by a specific mechanism called âMeiotic Silencing of Unsynapsed Chromatinâ (MSUC) in individuals with a partial or total spermatogenesis arrest (Turner et al., 2005). If some genes necessary for the proper course of meiosis are located in such unsynapsed genomic regions, MSUC may result in an arrest of the meiotic division. Secondly, associations between the âquadrivalentâ and the XY bivalent which is transcriptionally silenced by a phenomenon known as meiotic sex chromosome inactivation (MSCI, (Turner, 2007) were also observed in individuals with altered semen parameters (azoospermic or oligospemic) (Oliver-Bonet et al., 2005; Sciurano et al., 2007a, 2012). Such an association could result in a partial reactivation of the XY body (XYB) leading to the expression of some genes located on the X chromosome (Lifschytz and Lindsley, 1972), or result in the spreading of the XYB inactivation towards the autosomal segments attached to the XYB, without reactivation of the latter (Jaafar et al., 1993). Beyond the potential spermatogenesis failure mentioned above, reciprocal translocations are systematically responsible for the production of genetically unbalanced gametes. Here we report the detailed analysis of the whole meiotic process (from spermatocytes to spermatozoa) in the case of a constitutional balanced reciprocal translocation responsible for severe oligoasthenoteratospermia. Total RNA was extracted in 3 replicates from testicular biopsies control animals, from testicular biopsy of an oligospermic boar and from testicular biopsy of a severe oligo-astheno-teratospermic boar carrier of the trcp(1;14) reciprocal translocation.
2016-06-30 | E-GEOD-80693 | biostudies-arrayexpress
Project description:Spermatogenesis in the Drosophila male germline proceeds through a unique transcriptional program controlled both by germline-specific transcription factors and by testis-specific versions of core transcriptional machinery. This program includes the activation of genes on the heterochromatic Y chromosome, and reduced transcription from the X chromosome, but how expression from these sex chromosomes is regulated has not been defined. To resolve this, we profiled active chromatin features in the testes from wildtype and meiotic arrest mutants and integrate this with single-cell gene expression data from the Fly Cell Atlas. These data assign the timing of promoter activation for genes with germline-enriched expression throughout spermatogenesis, and general alterations of promoter regulation in germline cells. By profiling both active RNA polymerase II and histone modifications in isolated spermatocytes, we detail widespread patterns associated with regulation of the sex chromosomes. Our results demonstrate that the X chromosome is not enriched for silencing histone modifications, implying that sex chromosome inactivation does not occur in Drosophila. Instead, a lack of dosage compensation in spermatocytes accounts for the reduced expression from this chromosome. Finally, profiling uncovers dramatic ubiquitinylation of histone H2A and lysine-16 acetylation of histone H4 across the Y chromosome in spermatocytes that may contribute to the activation of this heterochromatic chromosome.
2023-10-04 | GSE225300 | GEO
Project description:We investigated the influence of extension of autosomal asynapsis on expression profiles during spermatogenesis. We used the mouse autosomal translocation T(16;17)43H (abbreviated T43H) and t12 haplotype, a natural variant of Chr 17 encompassing four adjacent non-overlapping inversions proximal to the T43H translocation breakpoint, as a model. The presence of t12 haplotype in trans to the T43H translocation resulted in stringent spermatogenic block and in more complete silencing of genes surrounding the T43H translocation break. Strikingly, silencing of the unsynapsed autosomal chromatin preceded the inactivation of the sex chromosomes (MSCI) and was apparent already in the population of pre-mid pachytene spermatocytes and testes of 15 days old males. Populations of pre-mid-pachytene spermatocytes were isolated from Ttf+/+T43H and t12+/+T43 males in three biological replicates. Their expression was compared to two biological replicates of the populations of pre-mid pachytene spermatocytes and mid-late pachytene spermatocytes obtained from C57BL/10J fertile males. Independently, testicular RNA was isolated from 15 days old Ttf+/+T43H and t12+/+T43 males in three biological replicates and the expression was compared to the testicular expression of two 15 days old C57BL/6J males.
2014-05-09 | E-GEOD-29177 | biostudies-arrayexpress
Project description:Dosage compensation in mammals involves silencing of one X chromosome in XX females, and requires expression, in cis, of Xist silencing RNA. Using microarray analysis to assay expression of X-linked genes in mouse embryonic stem cells, we show that dosage compensation also involves global up-regulation of expression from the active X in both males and females. Up-regulation is complete (ie. 2-fold) only after 2-3 weeks of differentiation. X-linked gene silencing in female cells occurs on a gene-by-gene basis throughout differentiation and includes a sub-group of genes silenced prior to the onset of differentiation and independently of enhanced Xist expression. Keywords: dosage compensation, gene silencing, Xist RNA, microarray
2007-12-01 | GSE8593 | GEO
Project description:Whole genome expression analyses reveal little evidence for X chromosome dosage compensation or meiotic inactivation in Drosophila testes, whereas testes-specific transgene reporters suggest a novel form of X chromosome-specific regulation.
2011-07-22 | GSE30850 | GEO