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PloS One 2014ATP-dependent nucleosome remodelers of the CHD family play important roles in chromatin regulation during development and differentiation. The ubiquitously expressed...
ATP-dependent nucleosome remodelers of the CHD family play important roles in chromatin regulation during development and differentiation. The ubiquitously expressed CHD3 and CHD4 proteins are essential for stem cell function and serve to orchestrate gene expression in different developmental settings. By contrast, the closely related CHD5 is predominantly expressed in neural tissue and its role is believed to be restricted to neural differentiation. Indeed, loss of CHD5 contributes to neuroblastoma. In this study, we first demonstrate that CHD5 is a nucleosome-stimulated ATPase. We then compare CHD3/4 and CHD5 expression in mouse brain and show that CHD5 expression is restricted to a subset of cortical and hippocampal neurons whereas CHD3/4 expression is more widespread. We also uncover high levels of CHD5 expression in testis. CHD5 is transiently expressed in differentiating germ cells. Expression is first detected in nuclei of post-meiotic round spermatids, reaches a maximum in stage VIII spermatids and then falls to undetectable levels in stage IX spermatids. Surprisingly, CHD3/4 and CHD5 show complementary expression patterns during spermatogenesis with CHD3/4 levels progressively decreasing as CHD5 expression increases. In spermatocytes, CHD3/4 localizes to the pseudoautosomal region, the X centromeric region and then spreads into the XY body chromatin. In postmeiotic cells, CHD5 colocalises with macroH2A1.2 in association with centromeres and part of the Y chromosome. The subnuclear localisations of CHD4 and CHD5 suggest specific roles in regulation of sex chromosome chromatin and pericentromeric chromatin structure prior to the histone-protamine switch.
Topics: Adenosine Triphosphatases; Animals; Brain; Cell Line; Cell Nucleus; Chromatids; Chromatin; DNA Helicases; Gene Expression Profiling; Gene Expression Regulation; In Situ Hybridization, Fluorescence; Male; Mice; Recombinant Proteins; Sex Chromosomes; Spermatocytes; Spermatogenesis; Testis
PubMed: 24849318
DOI: 10.1371/journal.pone.0098203 -
Genetics Sep 2018In most mammals, the X and Y chromosomes synapse and recombine along a conserved region of homology known as the pseudoautosomal region (PAR). These homology-driven...
In most mammals, the X and Y chromosomes synapse and recombine along a conserved region of homology known as the pseudoautosomal region (PAR). These homology-driven interactions are required for meiotic progression and are essential for male fertility. Although the PAR fulfills key meiotic functions in most mammals, several exceptional species lack PAR-mediated sex chromosome associations at meiosis. Here, we leveraged the natural variation in meiotic sex chromosome programs present in North American voles () to investigate the relationship between meiotic sex chromosome dynamics and X/Y sequence homology. To this end, we developed a novel, reference-blind computational method to analyze sparse sequencing data from flow-sorted X and Y chromosomes isolated from vole species with sex chromosomes that always (), never (), and occasionally synapse () at meiosis. Unexpectedly, we find more shared X/Y homology in the two vole species with no and sporadic X/Y synapsis compared to the species with obligate synapsis. Sex chromosome homology in the asynaptic and occasionally synaptic species is interspersed along chromosomes and largely restricted to low-complexity sequences, including a striking enrichment for the telomeric repeat sequence, TTAGGG. In contrast, homology is concentrated in high complexity, and presumably euchromatic, sequence on the X and Y chromosomes of the synaptic vole species, Taken together, our findings suggest key conditions required to sustain the standard program of X/Y synapsis at meiosis and reveal an intriguing connection between heterochromatic repeat architecture and noncanonical, asynaptic mechanisms of sex chromosome segregation in voles.
Topics: Animals; Arvicolinae; Chromosome Segregation; Genomics; Meiosis; North America; Pseudoautosomal Regions; Sequence Analysis, DNA; Sequence Homology, Nucleic Acid; Sex Chromosomes; Telomere; Telomere-Binding Proteins; X Chromosome; Y Chromosome
PubMed: 30002081
DOI: 10.1534/genetics.118.301182 -
Cellular and Molecular Life Sciences :... Mar 2023In mammals, meiotic recombination is initiated by the introduction of DNA double strand breaks (DSBs) into narrow segments of the genome, defined as hotspots, which is...
In mammals, meiotic recombination is initiated by the introduction of DNA double strand breaks (DSBs) into narrow segments of the genome, defined as hotspots, which is carried out by the SPO11/TOPOVIBL complex. A major player in the specification of hotspots is PRDM9, a histone methyltransferase that, following sequence-specific DNA binding, generates trimethylation on lysine 4 (H3K4me3) and lysine 36 (H3K36me3) of histone H3, thus defining the hotspots. PRDM9 activity is key to successful meiosis, since in its absence DSBs are redirected to functional sites and synapsis between homologous chromosomes fails. One protein factor recently implicated in guiding PRDM9 activity at hotspots is EWS, a member of the FET family of proteins that also includes TAF15 and FUS/TLS. Here, we demonstrate that FUS/TLS partially colocalizes with PRDM9 on the meiotic chromosome axes, marked by the synaptonemal complex component SYCP3, and physically interacts with PRDM9. Furthermore, we show that FUS/TLS also interacts with REC114, one of the axis-bound SPO11-auxiliary factors essential for DSB formation. This finding suggests that FUS/TLS is a component of the protein complex that promotes the initiation of meiotic recombination. Accordingly, we document that FUS/TLS coimmunoprecipitates with SPO11 in vitro and in vivo. The interaction occurs with both SPO11β and SPO11α splice isoforms, which are believed to play distinct functions in the formation of DSBs in autosomes and male sex chromosomes, respectively. Finally, using chromatin immunoprecipitation experiments, we show that FUS/TLS is localized at H3K4me3-marked hotspots in autosomes and in the pseudo-autosomal region, the site of genetic exchange between the XY chromosomes.
Topics: Animals; Male; Lysine; RNA-Binding Protein FUS; Histone-Lysine N-Methyltransferase; Homologous Recombination; DNA; Meiosis; Mammals
PubMed: 36967403
DOI: 10.1007/s00018-023-04744-5 -
Nature Jun 2020Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand...
Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation. How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.
Topics: Animals; Cell Cycle Proteins; Chromatin Assembly and Disassembly; Chromosome Pairing; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Female; Heterochromatin; Kinetics; Male; Meiosis; Mice; Minisatellite Repeats; Oocytes; Pseudoautosomal Regions; Recombination, Genetic; Sex Characteristics; Sister Chromatid Exchange; Spermatocytes; Ubiquitin-Protein Ligases
PubMed: 32461690
DOI: 10.1038/s41586-020-2327-4 -
Molecular Ecology Jul 2022Recombination strongly impacts sequence evolution by affecting the extent of linkage and the efficiency of selection. Here, we study recombination over the Z chromosome...
Recombination strongly impacts sequence evolution by affecting the extent of linkage and the efficiency of selection. Here, we study recombination over the Z chromosome in great reed warblers (Acrocephalus arundinaceus) using pedigree-based linkage mapping. This species has extended Z and W chromosomes ("neo-sex chromosomes") formed by a fusion between a part of chromosome 4A and the ancestral sex chromosomes, which provides a unique opportunity to assess recombination and sequence evolution in sex-linked regions of different ages. We assembled an 87.54 Mbp and 90.19 cM large Z with a small pseudoautosomal region (0.89 Mbp) at one end and the fused Chr4A-part at the other end of the chromosome. A prominent feature in our data was an extreme variation in male recombination rate along Z with high values at both chromosome ends, but an apparent lack of recombination over a substantial central section, covering 78% of the chromosome. The nonrecombining region showed a drastic loss of genetic diversity and accumulation of repeats compared to the recombining parts. Thus, our data emphasize a key role of recombination in affecting local levels of polymorphism. Nonetheless, the evolutionary rate of genes (dN/dS) did not differ between high and low recombining regions, suggesting that the efficiency of selection on protein-coding sequences can be maintained also at very low levels of recombination. Finally, the Chr4A-derived part showed a similar recombination rate as the part of the ancestral Z that did recombine, but its sequence characteristics reflected both its previous autosomal, and current Z-linked, recombination patterns.
Topics: Animals; Evolution, Molecular; Genetic Linkage; Male; Passeriformes; Polymorphism, Genetic; Recombination, Genetic; Sex Chromosomes
PubMed: 35578784
DOI: 10.1111/mec.16532 -
Reproduction, Nutrition, Development 1990The primary testis-determining function is exerted by a gene in the sex-determining region of the human Y chromosome. This gene is termed the sex-determining factor or... (Review)
Review
The primary testis-determining function is exerted by a gene in the sex-determining region of the human Y chromosome. This gene is termed the sex-determining factor or TDF. A zinc finger gene, ZFY, residing in this region has been cloned and characterized. It is a candidate for TDF. A challenge to future molecular research is to clarify the function of a zinc finger gene on the X chromosome, ZFX, that shows high structural similarity to ZFY. Furthermore, the existence of other genes involved in sex determination is likely but so far unproven. Sex reversal leading to testes in apparently XX individuals (XX males) is most often due to the presence of TDF on the paternally derived X chromosome. The abnormality arises during meiosis in the father when an abnormal exchange leads to the transfer onto the X of the entire pseudoautosomal region plus a portion of the Y chromosome-specific region including TDF from the Y. An XX male resulting from such an exchange is described. 10-20% of XX males do not have Y DNA. Two major mechanisms to explain such Y(-) XX males are discussed. First, several published pedigrees show clear-cut dominant autosomal or X chromosomal inheritance of XX maleness. These patients are always Y(-) and usually have sexual ambiguity. This indicates the existence of other genes, obviously 'downstream' from TDF, that when mutated can trigger testis determination. Nothing concrete is presently known about these putative genes, but their phenotypic effect is slightly different from that of TDF. Second, mosaicism with a prevalent XX lineage and a hidden or scarce lineage containing a Y chromosome can explain some apparently Y(-) XX males. Two XX/XXY mosaic patients are described in detail. In one, only a combination of DNA hybridization and cytogenetic studies led to the discovery of the XXY cell line. In conclusion, XX sex reversal in man is caused by at least 3 mechanisms, viz. abnormal Y-X interchange, genes other than TDF, and mosaicism.
Topics: Adolescent; DNA-Binding Proteins; Disorders of Sex Development; Female; Humans; Klinefelter Syndrome; Kruppel-Like Transcription Factors; Male; Middle Aged; Mosaicism; Polymorphism, Restriction Fragment Length; Sex Chromosome Aberrations; Sex Determination Analysis; Transcription Factors; Translocation, Genetic; Y Chromosome; Zinc Fingers
PubMed: 1976312
DOI: 10.1051/rnd:19900704 -
Blood Advances Aug 2018The Xg and CD99 antigens of the human Xg blood group system show a unique and sex-specific phenotypic relationship. The phenotypic relationship is believed to result...
The Xg and CD99 antigens of the human Xg blood group system show a unique and sex-specific phenotypic relationship. The phenotypic relationship is believed to result from transcriptional coregulation of the and genes, which span the pseudoautosomal boundary of the X and Y chromosomes. However, the molecular genetic background responsible for these blood groups has remained undetermined. During the present investigation, we initially conducted a pilot study aimed at individuals with different Xg/CD99 phenotypes; this used targeted next-generation sequencing of the genomic areas relevant to and This was followed by a large-scale association study that demonstrated a definite association between a single nucleotide polymorphism (SNP) rs311103 and the Xg/CD99 blood groups. The G and C genotypes of SNP rs311103 were associated with the Xg(a+)/CD99H and Xg(a-)/CD99L phenotypes, respectively. The rs311103 genomic region with the G genotype was found to have stronger transcription-enhancing activity by reporter assay, and this occurred specifically with erythroid-lineage cells. Such activity was absent when the same region with the C genotype was investigated. In silico analysis of the polymorphic rs311103 genomic regions revealed that a binding motif for members of the GATA transcription factor family was present in the rs311103[G] region. Follow-up investigations showed that the erythroid GATA1 factor is able to bind specifically to the rs311103[G] region and markedly stimulates the transcriptional activity of the rs311103[G] segment. The present findings identify the genetic basis of the erythroid-specific Xg/CD99 blood group phenotypes and reveal the molecular background of their formation.
Topics: 12E7 Antigen; Blood Group Antigens; Cell Adhesion Molecules; Chromosomes, Human, X; Chromosomes, Human, Y; Female; GATA1 Transcription Factor; Genotype; Humans; Male; Polymorphism, Single Nucleotide
PubMed: 30061310
DOI: 10.1182/bloodadvances.2018018879 -
Endocrine Connections May 2023The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in...
OBJECTIVE
The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs) obtained from patients with different genomic backgrounds and ethnicities.
DESIGN AND METHOD
We derived and characterized 15 iPSC lines from four Saudi 47,XXY KS patients and one Saudi 46,XY male. We performed a comparative transcriptional analysis using the Saudi KS-iPSCs and a cohort of European and North American KS-iPSCs.
RESULTS
We identified a panel of X-linked and autosomal genes commonly dysregulated in Saudi and European/North American KS-iPSCs vs 46,XY controls. Our findings demonstrate that seven PAR1 and nine non-PAR escape genes are consistently dysregulated and mostly display comparable transcriptional levels in both groups. Finally, we focused on genes commonly dysregulated in both iPSC cohorts and identified several gene-ontology categories highly relevant to KS physiopathology, including aberrant cardiac muscle contractility, skeletal muscle defects, abnormal synaptic transmission, and behavioral alterations.
CONCLUSIONS
Our results indicate that a transcriptomic signature of X chromosome overdosage in KS is potentially attributable to a subset of X-linked genes sensitive to sex chromosome dosage and escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic makeup.
PubMed: 36971776
DOI: 10.1530/EC-22-0515 -
Scientific Reports Jul 2023The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is...
The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is incompletely understood. Only a minor part of the QT interval variation in the general population has been linked to autosomal variant loci. Altered X chromosome dosage in humans, as seen in sex chromosome aneuploidies such as Turner syndrome (TS) and Klinefelter syndrome (KS), is associated with altered QTc interval (heart rate corrected QT), indicating that genes, located in the pseudoautosomal region 1 of the X and Y chromosomes may contribute to QT interval variation. We investigate the dosage effect of the pseudoautosomal gene SLC25A6, encoding the membrane ADP/ATP translocase 3 in the inner mitochondrial membrane, on QTc interval duration. To this end we used human participants and in vivo zebrafish models. Analyses in humans, based on 44 patients with KS, 44 patients with TS, 59 male and 22 females, revealed a significant negative correlation between SLC25A6 expression level and QTc interval duration. Similarly, downregulation of slc25a6 in zebrafish increased QTc interval duration with pharmacological inhibition of K channels restoring the systolic duration, whereas overexpression of SLC25A6 shortened QTc, which was normalized by pharmacological activation of K channels. Our study demonstrate an inverse relationship between SLC25A6 dosage and QTc interval indicating that SLC25A6 contributes to QT interval variation.
Topics: Animals; Female; Humans; Male; Adenosine Triphosphate; Electrocardiography; Klinefelter Syndrome; Long QT Syndrome; Turner Syndrome; X Chromosome; Zebrafish; Adenine Nucleotide Translocator 3
PubMed: 37495650
DOI: 10.1038/s41598-023-38867-3 -
Genome Biology and Evolution 2013Sex chromosome divergence has been documented across phylogenetically diverse species, with amphibians typically having cytologically nondiverged ("homomorphic") sex...
Sex chromosome divergence has been documented across phylogenetically diverse species, with amphibians typically having cytologically nondiverged ("homomorphic") sex chromosomes. With an aim of further characterizing sex chromosome divergence of an amphibian, we used "RAD-tags" and Sanger sequencing to examine sex specificity and heterozygosity in the Western clawed frog Silurana tropicalis (also known as Xenopus tropicalis). Our findings based on approximately 20 million genotype calls and approximately 200 polymerase chain reaction-amplified regions across multiple male and female genomes failed to identify a substantially sized genomic region with genotypic hallmarks of sex chromosome divergence, including in regions known to be tightly linked to the sex-determining region. We also found that expression and molecular evolution of genes linked to the sex-determining region did not differ substantially from genes in other parts of the genome. This suggests that the pseudoautosomal region, where recombination occurs, comprises a large portion of the sex chromosomes of S. tropicalis. These results may in part explain why African clawed frogs have such a high incidence of polyploidization, shed light on why amphibians have a high rate of sex chromosome turnover, and raise questions about why homomorphic sex chromosomes are so prevalent in amphibians.
Topics: Animals; Evolution, Molecular; Female; Gene Expression; Genotype; Male; Sex Chromosomes; Xenopus
PubMed: 23666865
DOI: 10.1093/gbe/evt073