Showing papers on "X chromosome published in 2018"
TL;DR: It is demonstrated that Toll-like receptor 7 (TLR7) that is encoded from the X chromosome escapes X inactivation in B cells and myeloid cells in females and Klinefelter individuals, and this finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with KlineFelter syndrome.
Abstract: Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. SLE prevalence is also elevated in individuals with Klinefelter syndrome, who carry one or more supernumerary X chromosomes, suggesting that the X chromosome complement contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and we examined here whether the TLR7 gene evades silencing by X chromosome inactivation in immune cells from women and Klinefelter syndrome males. Single-cell analyses of TLR7 allelic expression demonstrated that substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells not only in women but also in Klinefelter syndrome males express TLR7 on both X chromosomes. Biallelic B lymphocytes from women displayed greater TLR7 transcriptional expression than the monoallelic cells, correlated with higher TLR7 protein expression in female than in male leukocyte populations. Biallelic B cells were preferentially enriched during the TLR7-driven proliferation of CD27+ plasma cells. In addition, biallelic cells showed a greater than twofold increase over monoallelic cells in the propensity to immunoglobulin G class switch during the TLR7-driven, T cell-dependent differentiation of naive B lymphocytes into immunoglobulin-secreting cells. TLR7 escape from X inactivation endows the B cell compartment with added responsiveness to TLR7 ligands. This finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with Klinefelter syndrome.
354 citations
TL;DR: Current knowledge of the 3D organization of the mammalian X-chromosome chromatin is reviewed and its relationship with gene activity in light of the initiation, spreading, and maintenance of XCI, as well as escape from gene silencing is discussed.
Abstract: In somatic nuclei of female therian mammals, the two X chromosomes display very different chromatin states: One X is typically euchromatic and transcriptionally active, and the other is mostly sile...
170 citations
TL;DR: How the sex chromosome complement may influence obesity, lipid levels, and inflammation is discussed and the presence of two X chromosomes has been associated with increased adiposity and dyslipidemia in mouse models and in XXY men.
Abstract: Background Sex differences in obesity and related diseases are well established. Gonadal hormones are a major determinant of these sex differences. However, sex differences in body size and composition are evident prior to exposure to gonadal hormones, providing evidence for gonadal-independent contributions attributable to the XX or XY sex chromosome complement. Large-scale genetic studies have revealed male/female differences in the genetic architecture of adipose tissue amount and anatomical distribution. However, these studies have typically neglected the X and Y chromosomes. Scope of the review Here we discuss how the sex chromosome complement may influence obesity, lipid levels, and inflammation. Human sex chromosome anomalies such as Klinefelter syndrome (XXY), as well as mouse models with engineered alterations in sex chromosome complement, support an important role for sex chromosomes in obesity and metabolism. In particular, the Four Core Genotypes mouse model—consisting of XX mice with either ovaries or testes, and XY mice with either ovaries or testes—has revealed an effect of X chromosome dosage on adiposity, hyperlipidemia, and inflammation irrespective of male or female gonads. Mechanisms may include enhanced expression of genes that escape X chromosome inactivation. Major conclusions Although less well studied than effects of gonadal hormones, sex chromosomes exert independent and interactive effects on adiposity, lipid metabolism, and inflammation. In particular, the presence of two X chromosomes has been associated with increased adiposity and dyslipidemia in mouse models and in XXY men. The enhanced expression of genes that escape X chromosome inactivation may contribute, but more work is required.
111 citations
TL;DR: Recent advances in the understanding of the role of Xist in X chromosome dosage compensation in mouse and human are discussed.
103 citations
TL;DR: Recent advances are reviewed, which reveal a complex interplay among lncRNAs, the chromatin landscape, transcription, and chromosome conformation that fine-tune X chromosome gene expression.
Abstract: X chromosome regulation represents a prime example of an epigenetic phenomenon where coordinated regulation of a whole chromosome is required. In flies, this is achieved by transcriptional upregula...
97 citations
TL;DR: It is shown that large-scale chromosome folding patterns and levels of chromosome intermixing are remarkably stable across various cell types and that the nucleus scales to accommodate fluctuations in chromosome size throughout the cell cycle, which limits the degree of inter mixing between neighboring CTs.
Abstract: Metazoan chromosomes are folded into discrete sub-nuclear domains, referred to as chromosome territories (CTs). The molecular mechanisms that underlie the formation and maintenance of CTs during the cell cycle remain largely unknown. Here, we have developed high-resolution chromosome paints to investigate CT organization in Drosophila cycling cells. We show that large-scale chromosome folding patterns and levels of chromosome intermixing are remarkably stable across various cell types. Our data also suggest that the nucleus scales to accommodate fluctuations in chromosome size throughout the cell cycle, which limits the degree of intermixing between neighboring CTs. Finally, we show that the cohesin and condensin complexes are required for different scales of chromosome folding, with condensin II being especially important for the size, shape, and level of intermixing between CTs in interphase. These findings suggest that large-scale chromosome folding driven by condensin II influences the extent to which chromosomes interact, which may have direct consequences for cell-type specific genome stability.
86 citations
TL;DR: The study reveals that the X chromosome protects against BCa among females via a KDM6A-dependent epigenetic mechanism and further suggests that KDM 6A is a prototypical sex-biasing tumor suppressor with both demethylase-dependent and dem methylase-independent activities.
Abstract: Men are much more likely than women to develop bladder cancer (BCa), but the underlying cause of this gender disparity remains poorly defined. Using sex-reversed mice, we show that the sex chromosome complement is an independent cause and, moreover, amplifies the biasing effects of sex hormones. We also show that the X-linked lysine demethylase 6A (KDM6A) is a sexually dimorphic gene. Wild-type but not catalytically dead KDM6A confers sustained tumor suppressor activity in vitro. Knockout of mouse Kdm6a reduces expression of Cdkn1a and Perp, canonical gene targets of the tumor suppressor p53. Consistently, loss of Kdm6a increases BCa risk in female mice, and mutations or reduced expression of human KDM6A predicts poor prognosis of female BCa patients. Collectively, the study reveals that the X chromosome protects against BCa among females via a KDM6A-dependent epigenetic mechanism and further suggests that KDM6A is a prototypical sex-biasing tumor suppressor with both demethylase-dependent and demethylase-independent activities.
82 citations
TL;DR: It is found that this effect is associated with cell-cycle phases and, independently, with the XIST expression level, which is higher in the quiescent phase (G0).
Abstract: X-chromosome inactivation (XCI) provides a dosage compensation mechanism where, in each female cell, one of the two X chromosomes is randomly silenced. However, some genes on the inactive X chromosome and outside the pseudoautosomal regions escape from XCI and are expressed from both alleles (escapees). We investigated XCI at single-cell resolution combining deep single-cell RNA sequencing with whole-genome sequencing to examine allelic-specific expression in 935 primary fibroblast and 48 lymphoblastoid single cells from five female individuals. In this framework we integrated an original method to identify and exclude doublets of cells. In fibroblast cells, we have identified 55 genes as escapees including five undescribed escapee genes. Moreover, we observed that all genes exhibit a variable propensity to escape XCI in each cell and cell type and that each cell displays a distinct expression profile of the escapee genes. A metric, the Inactivation Score-defined as the mean of the allelic expression profiles of the escapees per cell-enables us to discover a heterogeneous and continuous degree of cellular XCI with extremes represented by "inactive" cells, i.e., cells exclusively expressing the escaping genes from the active X chromosome and "escaping" cells expressing the escapees from both alleles. We found that this effect is associated with cell-cycle phases and, independently, with the XIST expression level, which is higher in the quiescent phase (G0). Single-cell allele-specific expression is a powerful tool to identify novel escapees in different tissues and provide evidence of an unexpected cellular heterogeneity of XCI.
70 citations
TL;DR: Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS, and point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes,Which may be involved in X chromosome inactivation in KS.
Abstract: Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.
68 citations
TL;DR: A mixed modality approach that combines a small-molecule inhibitor of DNA methylation and an antisense oligonucleotide against Xist RNA achieves up to 30,000-fold methyl-CpG binding protein 2 upregulation in cultured cells, providing proof of concept for a mixedmodality approach for treating X-linked disorders in females.
Abstract: The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Because female cells carry two X chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here, we focus on methyl-CpG binding protein 2 (MECP2) restoration for RTT and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small-molecule inhibitor of DNA methylation, which, together, achieve 30,000-fold MECP2 up-regulation from the Xi in cultured cells. Combining a brain-specific genetic Xist ablation with short-term 5-aza-2'-deoxycytidine (Aza) treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females.
66 citations
TL;DR: DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes, and TERT alterations and DMD inactivation were mutually independent in predicting unfavorable outcomes.
Abstract: Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3–9.0) vs. median not reached (95% CI 2.9–not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1–TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0–6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5–9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
TL;DR: The state of the art of knowledge on the implication of miRs encoded on sex chromosomes, and their related functional paths, in the regulation of cell homeostasis are analyzed and possible perspectives for the epigenetic research in the field are depicted.
Abstract: A sexual dimorphism at the cellular level has been suggested to play a role in cancer onset and progression. In particular, very recent studies have unraveled striking differences between cells carrying XX or XY chromosomes in terms of response to stressful stimuli, indicating the presence of genetic and epigenetic differences determining sex-specific metabolic or phenotypic traits. Although this field of investigation is still in its infancy, available data suggest a key role of sexual chromosomes in determining cell life or death. In particular, cells carrying XX chromosomes exhibit a higher adaptive potential and survival behavior in response to microenvironmental variations with respect to XY cells. Cells from females also appear to be equipped with more efficient epigenetic machinery than the male counterpart. In particular, the X chromosome contains an unexpected high number of microRNAs (miRs), at present 118, in comparison with only two miRs localized on chromosome Y, and an average of 40-50 on the autosomes. The regulatory power of these small non-coding RNAs is well recognized, as 30-50% of all protein-coding genes are targeted by miRs and their role in cell fate has been well demonstrated. In addition, several further insights, including DNA methylation patterns that are different in males and females, claim for a significant gender disparity in cancer and in the immune system activity against tumors. In this brief paper, we analyze the state of the art of our knowledge on the implication of miRs encoded on sex chromosomes, and their related functional paths, in the regulation of cell homeostasis and depict possible perspectives for the epigenetic research in the field.
TL;DR: In this review, recent advances in understanding of the genetics and epigenetics of the X chromosome are discussed and there is growing recognition that escapees contribute to sexually dimorphic traits.
Abstract: The X chromosome is unique in the genome. In this review we discuss recent advances in our understanding of the genetics and epigenetics of the X chromosome. The X chromosome shares limited conservation with its ancestral homologue the Y chromosome and the resulting difference in X-chromosome dosage between males and females is largely compensated for by X-chromosome inactivation. The process of inactivation is initiated by the long non-coding RNA X-inactive specific transcript (XIST) and achieved through interaction with multiple synergistic silencing pathways. Identification of Xist-interacting proteins has given insight into these processes yet the cascade of events from initiation to maintenance have still to be resolved. In particular, the initiation of inactivation in humans has been challenging to study as: it occurs very early in development; most human embryonic stem cell lines already have an inactive X; and the process seems to differ from mouse. Another difference between human and mouse X inactivation is the larger number of human genes that escape silencing. In humans over 20% of X-linked genes continue to be expressed from the otherwise inactive X chromosome. We are only beginning to understand how such escape occurs but there is growing recognition that escapees contribute to sexually dimorphic traits. The unique biology and epigenetics of the X chromosome have often led to its exclusion from disease studies, yet the X constitutes 5% of the genome and is an important contributor to disease, often in a sex-specific manner.
TL;DR: It is proposed that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
Abstract: Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10−7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
TL;DR: It is shown that SETDB1 imposes timely expression of meiotic and post-meiotic genes, which unites the DDR network, asynapsis, and meiotic chromosome silencing.
TL;DR: It is proved that nullification of the XIST gene in donor cells can normalize aberrant gene expression in cloned embryos and enhance long-term development capacity of the embryos.
Abstract: Summary Pig cloning by somatic cell nuclear transfer (SCNT) remains extremely inefficient, and many cloned embryos undergo abnormal development. Here, by profiling transcriptome expression, we observed dysregulated chromosome-wide gene expression in every chromosome and identified a considerable number of genes that are aberrantly expressed in the abnormal cloned embryos. In particular, XIST , a long non-coding RNA gene, showed high ectopic expression in abnormal embryos. We also proved that nullification of the XIST gene in donor cells can normalize aberrant gene expression in cloned embryos and enhance long-term development capacity of the embryos. Furthermore, the increased quality of XIST -deficient embryos was associated with the global H3K9me3 reduction. Injection of H3K9me demethylase Kdm4A into NT embryos could improve the development of pre-implantation stage embryos. However, Kdm4A addition also induced XIST derepression in the active X chromosome and thus was not able to enhance the in vivo long-term developmental capacity of porcine NT embryos.
TL;DR: Functional evidence is provided that pfpdz1 is significant for male differentiation and maintenance in yellow catfish and initiates testicular differentiation through upregulating expression of amh, dmrt1 and sox9a1, as well as downregulatingexpression of cyp19a 1, foxl2 and wnt4.
Abstract: The sex-determining genes are found to be variable among different fish species. Yellow catfish (Pelteobagrus fulvidraco) is an important aquaculture fish species in China with XX/XY sex-determining type. Recently, YY super-male yellow catfish has been successfully produced by combining hormonal-induced sex reversal method with sex chromosome-linked markers. Here, we identified a novel PDZ domain-containing gene in yellow catfish designated as pfpdz1, in whose intron the sex-linked marker was located. The coding sequence of pfpdz1 in Y chromosome was identical to that in X chromosome except a missense SNP (A/T) that changes an amino acid (E8V) in the N-terminal region. Pfpdz1 displayed male-specific expression during sex differentiation. Overexpression of pfpdz1 using additive transgenesis induces XX ovary to differentiate into testis-like tissue, while the targeted inactivation of pfpdz1 in Y chromosome using CRISPR/Cas9-mediated mutagenesis triggers ovarian differentiation. Furthermore, we demonstrated that pfpdz1 initiates testicular differentiation through upregulating expression of amh, dmrt1 and sox9a1, as well as downregulating expression of cyp19a1, foxl2 and wnt4. Our data provide functional evidence that pfpdz1 is significant for male differentiation and maintenance in yellow catfish.
TL;DR: By combining parental haplotype reconstruction with single-cell transcriptomics of human female embryonic germ cells, the authors demonstrate that epigenetic reprogramming occurs in a heterogeneous fashion and during a broad time window up to week 14.
Abstract: In contrast to mouse, human female germ cells develop asynchronously. Germ cells transition to meiosis, erase genomic imprints, and reactivate the X chromosome. It is unknown if these events all appear asynchronously, and how they relate to each other. Here we combine exome sequencing of human fetal and maternal tissues with single-cell RNA-sequencing of five donors. We reconstruct full parental haplotypes and quantify changes in parental allele-specific expression, genome-wide. First we distinguish primordial germ cells (PGC), pre-meiotic, and meiotic transcriptional stages. Next we demonstrate that germ cells from various stages monoallelically express imprinted genes and confirm this by methylation patterns. Finally, we show that roughly 30% of the PGCs are still reactivating their inactive X chromosome and that this is related to transcriptional stage rather than fetal age. Altogether, we uncover the complexity and cell-to-cell heterogeneity of transcriptional and epigenetic remodeling in female human germ cells.
TL;DR: Fish have a high diversity of sex-determining systems, but the mechanisms responsible for this are not well understood, and it is experimentally demonstrated that hybridisation can catalyze rapid evolution of a new sex chromosome.
Abstract: The remarkable diversity of sex determination mechanisms known in fish may be fuelled by exceptionally high rates of sex chromosome turnovers or transitions. However, the evolutionary causes and genomic mechanisms underlying this variation and instability are yet to be understood. Here we report on an over 30-year evolutionary experiment in which we tested the genomic consequences of hybridisation and selection between two Xiphophorus fish species with different sex chromosome systems. We find that introgression and imposing selection for pigmentation phenotypes results in the retention of an unexpectedly large maternally derived genomic region. During the hybridisation process, the sex-determining region of the X chromosome from one parental species was translocated to an autosome in the hybrids leading to the evolution of a new sex chromosome. Our results highlight the complexity of factors contributing to patterns observed in hybrid genomes, and we experimentally demonstrate that hybridisation can catalyze rapid evolution of a new sex chromosome.
TL;DR: The results indicate that the sexes of S. argus are controlled by sex chromosomes (XX females, XY males), and Dmrt1 is highly expressed in the testes, while it is not expression in the ovaries.
TL;DR: Five of the better-known sex aneuploidies are discussed: Turner syndrome (XO), Klinefelter syndrome (XXY), trisomy X (XXX), XYY, and XXYY, which have a characteristic physical, cognitive, and neurologic profile.
Abstract: Sex chromosome aneuploidies comprise a relatively common group of chromosome disorders characterized by the loss or gain of one or more sex chromosomes. We discuss five of the better-known sex aneuploidies: Turner syndrome (XO), Klinefelter syndrome (XXY), trisomy X (XXX), XYY, and XXYY. Despite their prevalence in the general population, these disorders are underdiagnosed and the specific genetic mechanisms underlying their phenotypes are poorly understood. Although there is considerable variation between them in terms of associated functional impairment, each disorder has a characteristic physical, cognitive, and neurologic profile. The most common cause of sex chromosome aneuploidies is nondisjunction, which can occur during meiosis or during the early stages of postzygotic development. The loss or gain of genetic material can affect all daughter cells or it may be partial, leading to tissue mosaicism. In both typical and atypical sex chromosome karyotypes, there is random inactivation of all but one X chromosome. The mechanisms by which a phenotype results from sex chromosome aneuploidies are twofold: dosage imbalance arising from a small number of genes that escape inactivation, and their endocrinologic consequences.
TL;DR: These findings suggest the existence of mechanisms that enable a shift in gene expression during prophase I to promote germ cell progression and find that a large fraction of genes may bypass the need for CSR-1-mediated germline licensing.
Abstract: Developmental programs are executed by tightly controlled gene regulatory pathways. Here, we combined the unique sample retrieval capacity afforded by laser capture microscopy with analysis of mRNA abundance by CEL-Seq (cell expression by linear amplification and sequencing) to generate a spatiotemporal gene expression map of the Caenorhabditis elegans syncytial germline from adult hermaphrodites and males. We found that over 6000 genes exhibit spatiotemporally dynamic expression patterns throughout the hermaphrodite germline, with two dominant groups of genes exhibiting reciprocal shifts in expression at late pachytene during meiotic prophase I. We found a strong correlation between restricted spatiotemporal expression and known developmental and cellular processes, indicating that these gene expression changes may be an important driver of germ cell progression. Analysis of the male gonad revealed a shift in gene expression at early pachytene and upregulation of subsets of genes following the meiotic divisions, specifically in early and late spermatids, mostly transcribed from the X chromosome. We observed that while the X chromosome is silenced throughout the first half of the gonad, some genes escape this control and are highly expressed throughout the germline. Although we found a strong correlation between the expression of genes corresponding to CSR-1-interacting 22G-RNAs during germ cell progression, we also found that a large fraction of genes may bypass the need for CSR-1-mediated germline licensing. Taken together, these findings suggest the existence of mechanisms that enable a shift in gene expression during prophase I to promote germ cell progression.
TL;DR: The dispute between the meiotic and post-zygotic origins of 45, X monosomy is reviewed, by mainly analyzing the findings from several studies that compare gene expression of the 45,Xmonosomy to their euploid and/or 47,XXX trisomic cell counterparts on peripheral blood mononuclear cells, amniotic fluid, human fibroblast cells, and induced pluripotent human cell lines.
Abstract: Monosomy of the X chromosome is the most frequent genetic abnormality in human as it is present in approximately 2% of all conceptions, although 99% of these embryos are spontaneously miscarried. In postnatal life, clinical features of Turner syndrome may include typical dysmorphic stigmata, short stature, sexual infantilism, and renal, cardiac, skeletal, endocrine and metabolic abnormalities. Turner syndrome is due to a partial or total loss of the second sexual chromosome, resulting in the development of highly variable clinical features. This phenotype may not merely be due to genomic imbalance from deleted genes but may also result from additive influences on associated genes within a given gene network, with an altered regulation of gene expression triggered by the absence of the second sex chromosome. Current studies in human and mouse models have demonstrated that this chromosomal abnormality leads to epigenetic changes, including differential DNA methylation in specific groups of downstream target genes in pathways associated with several clinical and metabolic features, mostly on autosomal chromosomes. In this article, we begin exploring the potential involvement of both genetic and epigenetic factors in the origin of X chromosome monosomy. We review the dispute between the meiotic and post-zygotic origins of 45,X monosomy, by mainly analyzing the findings from several studies that compare gene expression of the 45,X monosomy to their euploid and/or 47,XXX trisomic cell counterparts on peripheral blood mononuclear cells, amniotic fluid, human fibroblast cells, and induced pluripotent human cell lines. From these studies, a profile of epigenetic changes seems to emerge in response to chromosomal imbalance. An interesting finding of all these studies is that methylation-based and expression-based pathway analyses are complementary, rather than overlapping, and are correlated with the clinical picture displayed by TS subjects. The clarification of these possible causal pathways may have future implications in increasing the life expectancy of these patients and may provide informative targets for early pharmaceutical intervention.
TL;DR: An XY sex chromosome complement mediates diffuse aortic pathology, whereas an XX sex chromosomes complement contributes to focal AngII-induced AAAs.
Abstract: Objective—Aortic pathologies exhibit sexual dimorphism, with aneurysms in both the thoracic and abdominal aorta (ie, abdominal aortic aneurysm [AAA]) exhibiting higher male prevalence. Women have lower prevalence of aneurysms, but when they occur, aneurysms progress rapidly. To define mechanisms for these sex differences, we determined the role of sex chromosome complement and testosterone on the location and progression of angiotensin II (AngII)–induced aortic pathologies. Approach and Results—We used transgenic male mice expressing Sry (sex-determining region Y) on an autosome to create Ldlr (low-density lipoprotein receptor)–deficient male mice with an XY or XX sex chromosome complement. Transcriptional profiling was performed on abdominal aortas from XY or XX males, demonstrating 1746 genes influenced by sex chromosomes or sex hormones. Males (XY or XX) were either sham-operated or orchiectomized before AngII infusions. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, whereas XX ...
TL;DR: It is proposed that XCI initiation is gender independent and triggered by destabilization of naive identity, suggesting that gender-specific mechanisms follow, rather than precede, X CI initiation.
TL;DR: It is demonstrated that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI, and an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver is validated, supporting a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation.
Abstract: DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome-wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses.
TL;DR: A study finds a novel mechanism of plant dosage compensation, where genomic imprinting results in higher expression from the maternal X chromosome in both males and females, by examining the evolutionarily young XY sex determination system of Silene latifolia.
Abstract: Sex chromosomes have repeatedly evolved from a pair of autosomes. Consequently, X and Y chromosomes initially have similar gene content, but ongoing Y degeneration leads to reduced expression and eventual loss of Y genes1. The resulting imbalance in gene expression between Y genes and the rest of the genome is expected to reduce male fitness, especially when protein networks have components from both autosomes and sex chromosomes. A diverse set of dosage compensating mechanisms that alleviates these negative effects has been described in animals2–4. However, the early steps in the evolution of dosage compensation remain unknown, and dosage compensation is poorly understood in plants5. Here, we describe a dosage compensation mechanism in the evolutionarily young XY sex determination system of the plant Silene latifolia. Genomic imprinting results in higher expression from the maternal X chromosome in both males and females. This compensates for reduced Y expression in males, but results in X overexpression in females and may be detrimental. It could represent a transient early stage in the evolution of dosage compensation. Our finding has striking resemblance to the first stage proposed by Ohno6 for the evolution of X inactivation in mammals. A study finds a novel mechanism of plant dosage compensation, where genomic imprinting results in higher expression of maternal X chromosomes, by examining the evolutionarily young XY sex determination system of Silene latifolia.
TL;DR: The results reveal the early stages of Y chromosome divergence in the guppy and identify a male-specific sequence shared between P. reticulata and P. wingei consistent with a small ancestral non-recombining region.
Abstract: Sex chromosomes form once recombination is halted around the sex-determining locus between a homologous pair of chromosomes, resulting in a male-limited Y chromosome. We recently characterized the nascent sex chromosome system in the Trinidadian guppy (Poeciliareticulata). The guppy Y is one of the youngest animal sex chromosomes yet identified, and therefore offers a unique window into the early evolutionary forces shaping sex chromosome formation, particularly the rate of accumulation of repetitive elements and Y-specific sequence. We used comparisons between male and female genomes in P. reticulata and its sister species, Endler’s guppy (P. wingei), which share an ancestral sex chromosome, to identify male-specific sequences and to characterize the degree of differentiation between the X and Y chromosomes. We identified male-specific sequence shared between P. reticulata and P. wingei consistent with a small ancestral non-recombining region. Our assembly of this Y-specific sequence shows substantial homology to the X chromosome, and appears to be significantly enriched for genes implicated in pigmentation. We also found two plausible candidates that may be involved in sex determination. Furthermore, we found that the P. wingei Y chromosome exhibits a greater signature of repetitive element accumulation than the P. reticulata Y chromosome. This suggests that Y chromosome divergence does not necessarily correlate with the time since recombination suppression. Overall, our results reveal the early stages of Y chromosome divergence in the guppy.
TL;DR: This study revealed that admixture of the two opposite sex‐chromosome systems reconstructed a female heterogametic system by recycling the X chromosomes into new W chromosomes, offering an illustrative example of how de novo sex‐ chromosome systems can arise by recycling material from ancestral sex chromosomes.
Abstract: Sex-determining mechanisms change repeatedly throughout evolution, and it is difficult to track this continual process. The Japanese soil-frog Glandirana rugosa is a remarkable evolutionary witness to the ongoing process of the evolution of sex-determining modes. The two geographic groups, designated XY and Neo-ZW, have homologous sex chromosomes, yet display opposite types of sex chromosomes, XX-XY and ZZ-ZW, respectively. These two groups are sympatric at the edges of their respective ranges in Central Japan. In this study, we discovered molecular evidence that the eastern part of the Neo-ZW group (Neo-ZW2 subgroup), which is found near the sympatric area, shares mitochondrial haplotypes with the XY group. By analysing single nucleotide polymorphism (SNP) loci, we have also discovered that the representative nuclear genome of the Neo-ZW2 subgroup shares allele clusters with both the XY group and another part of the Neo-ZW group (Neo-ZW1 subgroup), indicating a hybrid origin of the Neo-ZW2. Further analysis of sex-linked SNP loci revealed that the alleles on the W chromosomes of the Neo-ZW2 were derived mostly from X chromosomes, while alleles on the Z chromosomes originated from the Z chromosomes of the Neo-ZW1 subgroup and partly from the Y chromosomes of the XY group. Our study revealed that admixture of the two opposite sex-chromosome systems reconstructed a female heterogametic system by recycling the X chromosomes into new W chromosomes. This work offers an illustrative example of how de novo sex-chromosome systems can arise by recycling material from ancestral sex chromosomes.
TL;DR: How evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes is explained and new research uncovering unusual X dosage compensation states in germ cells are discussed, which are postulate to influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy.
Abstract: Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy.