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Diagnosing skin diseases in children can be a complex interdisciplinary problem. Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare hereditary genodermatosis related to a mutation in the IKBKG gene. We present a family case of IP described from the perspective of various specialists, including dermatologists, oncologists, geneticists, dentists, and trichologists. The peculiarity of this case is the development of squamous cell carcinoma (SCC) on the shin of a 10-year-old female patient with IP. The patient had a positive family history: her mother and two sisters also displayed clinical manifestations of IP with involvement of skin, teeth and hair. The presence of exons 4-10 deletion in the IKBKG gene in all affected females was confirmed by detailed genetic evaluation using long-range PCR, and also high degree of X-chromosome inactivation skewing was demonstrated. The family underwent a comprehensive examination and was followed up for 2 years with successful symptomatic treatment of dermatologic manifestations. Recommendations were also made regarding dental and hair problems. By the end of the follow-up period, patients had stabilized, with the exception of a 36-year-old mother who developed generalized morphea. The study demonstrates the varying expressiveness of clinical symptoms among family members and emphasizes the importance of timely diagnosis for effective management of patients with IP.
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Turner syndrome (TS) is a female phenotypic condition characterized by one or more typical clinical features and the partial or complete absence of a second X chromosome as determined by karyotype analysis. TS, among the most common chromosomal abnormalities, has an estimated prevalence of approximately 1 in 2,500 live-born females, with ethnic and racial differences. TS encompasses a wide array of medical challenges, including cardiovascular, endocrine, autoimmune, and mental health issues, as well as a heightened cancer risk. The somatic stigmata of TS are thought to arise from haploinsufficiency of the X chromosomes. This review explores the lifelong medical challenges and immunogenetics of individuals with TS and aimed to investigate strategies for preventing and managing TS while considering the implications of immunogenetics.
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Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell-derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome-linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
Sex differences are a contributing factor in neuropsychiatric conditions such as autism, which is more prevalent in males. Sex differences occur through interactions between sex steroid hormones such as estrogen and testosterone and sex chromosomes (chrX and chrY). Human stem cellderived brain organoids are laboratory models that mimic brain development. For example, in individuals with neurodevelopmental conditions, brain organoids have revealed an imbalance of neuron populations compared with neurotypical individuals. In this review, we discuss sex steroid and sex chromosome influences on brain development and challenges of this model that need to be taken into account when studying sex differences.
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Changes in gene dosage can have tremendous evolutionary potential (e.g. whole-genome duplications), but without compensatory mechanisms, they can also lead to gene dysregulation and pathologies. Sex chromosomes are a paradigmatic example of naturally occurring gene dosage differences and their compensation. In species with chromosome-based sex determination, individuals within the same population necessarily show 'natural' differences in gene dosage for the sex chromosomes. In this Review, we focus on the mammalian X chromosome and discuss recent new insights into the dosage-compensation mechanisms that evolved along with the emergence of sex chromosomes, namely X-inactivation and X-upregulation. We also discuss the evolution of the genetic loci and molecular players involved, as well as the regulatory diversity and potentially different requirements for dosage compensation across mammalian species.
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Compensación de Dosificación (Genética) , Mamíferos , Inactivación del Cromosoma X , Cromosoma X , Animales , Humanos , Cromosoma X/genética , Mamíferos/genética , Inactivación del Cromosoma X/genética , Dosificación de Gen , Evolución MolecularRESUMEN
BACKGROUND AND HYPOTHESIS: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. Female patients, however, show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. However, the factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort. METHODS: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leukocytes using the human androgen receptor assay method and analyzed two cohorts. In 74 adult female patients, we evaluated the correlation between kidney function (creatinine-estimated glomerular filtration rate [Cr-eGFR] optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis, and in 65 pediatric female patients, we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein-to-creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazard analysis. RESULTS: In adult female patients, XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate = -0.53, P = 0.004), whereas genotype was not (P = 0.892). In pediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria (hazard ratio [HR], 3.702; 95% confidence interval [CI], 1.681-8.150; P = 0.001 and HR, 1.043; 95% CI, 1.061-1.070; P = 0.001, respectively), whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = 0.20, P = 0.67, respectively). CONCLUSION: Genotype and XCI are factors associated with the severity in females with XLAS.
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Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist's ability to diffuse under select circumstances has also been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that Xist RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. Xist binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human XIST RNA. We find that Xist binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing Xist in transgenic ES cells similarly lead to autosomal gene suppression, while deleting Xist's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the Xist inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal Xist targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by the X1 small molecule inhibitor.
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Analysis of clonal dynamics in human tissues is enabled by somatic genetic variation. Here, we show that analysis of mitochondrial mutations in single cells is dramatically improved in females when using X chromosome inactivation to select informative clonal mutations. Applying this strategy to human peripheral mononuclear blood cells reveals clonal structures within T cells that otherwise are blurred by non-informative mutations, including the separation of gamma-delta T cells, suggesting this approach can be used to decipher clonal dynamics of cells in human tissues.
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Mutación , Análisis de la Célula Individual , Inactivación del Cromosoma X , Humanos , Femenino , Leucocitos Mononucleares/metabolismo , Cromosomas Humanos X/genética , Células Clonales , Linfocitos T/metabolismo , Masculino , ADN Mitocondrial/genéticaRESUMEN
Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.
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A significant source of risk for neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorder (ASD), lies in genes located on the X chromosome. Males can be particularly vulnerable to X-linked variation because of hemizygosity, and male-specific segregation in pedigrees has guided earlier gene discovery for X-linked recessive conditions. More recently, X-linked disorders disproportionally affecting females, with complex inheritance patterns and/or presenting with sex differences, have surfaced. Here, we discuss the genetics and neurobiology of X-linked genes that are paradigmatic to understand NDDs in females. Integrating genetic, clinical, and functional data will be key to understand how X-linked variation contributes to the risk architecture of NDDs.
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Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.
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BACKGROUND: Duplications on the short arm of chromosome X, including the gene NR0B1, have been associated with gonadal dysgenesis and with male to female sex reversal. Additional clinical manifestations can be observed in the affected patients, depending on the duplicated genomic region. Here we report one of the largest duplications on chromosome X, in a Lebanese patient, and we provide the first comprehensive review of duplications in this genomic region. CASE PRESENTATION: A 2-year-old female patient born to non-consanguineous Lebanese parents, with a family history of one miscarriage, is included in this study. The patient presents with sex reversal, dysmorphic features, optic atrophy, epilepsy, psychomotor and neurodevelopmental delay. Single nucleotide variants and copy number variants analysis were carried out on the patient through exome sequencing (ES). This showed an increased coverage of a genomic region of around 23.6 Mb on chromosome Xp22.31-p21.2 (g.7137718-30739112) in the patient, suggestive of a large duplication encompassing more than 60 genes, including the NR0B1 gene involved in sex reversal. A karyotype analysis confirmed sex reversal in the proband presenting with the duplication, and revealed a balanced translocation between the short arms of chromosomes X and 14:46, X, t(X;14) (p11;p11) in her/his mother. CONCLUSIONS: This case highlights the added value of CNV analysis from ES data in the genetic diagnosis of patients. It also underscores the challenges encountered in announcing unsolicited incidental findings to the family.
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Variaciones en el Número de Copia de ADN , Epilepsia , Secuenciación del Exoma , Trastornos del Neurodesarrollo , Atrofia Óptica , Preescolar , Humanos , Duplicación Cromosómica/genética , Cromosomas Humanos X/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Epilepsia/genética , Epilepsia/patología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Atrofia Óptica/genética , Atrofia Óptica/patologíaRESUMEN
X chromosome centromeric drive may explain the prevalence of polycystic ovary syndrome and contribute to oocyte aneuploidy, menopause, and other conditions. The mammalian X chromosome may be vulnerable to meiotic drive because of X inactivation in the female germline. The human X pericentromeric region contains genes potentially involved in meiotic mechanisms, including multiple SPIN1 and ZXDC paralogs. This is consistent with a multigenic drive system comprising differential modification of the active and inactive X chromosome centromeres in female primordial germ cells and preferential segregation of the previously inactivated X chromosome centromere to the polar body at meiosis I. The drive mechanism may explain differences in X chromosome regulation in the female germlines of the human and mouse and, based on the functions encoded by the genes in the region, the transmission of X pericentromeric genetic or epigenetic variants to progeny could contribute to preeclampsia, autism, and differences in sexual differentiation.
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BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic disorder caused by aberrant motile cilia function that results in defective ciliary airway clearance and subsequently to recurrent airway infections and bronchiectasis. QUESTION: How many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance? METHODS: To answer this question we exploited the molecular defects of the X-linked recessive PCD variant caused by pathogenic variants in DNAAF6 (PIH1D3), characterized by immotile cilia in the affected males. We carefully analyzed the clinical phenotype, molecular defect (immunofluorescence and transmission-electron microscopy) and performed in vitro (particle tracking in air-liquid interface cultures) and in vivo (radiolabeled tracer studies) studies to assess ciliary clearance of respiratory cells from females with heterozygous and males with hemizygous pathogenic DNAAF6 variants. RESULTS: PCD males with hemizygous pathogenic DNAAF6 variants displayed exclusively immotile cilia, absence of ciliary clearance and severe PCD symptoms. Due to random or skewed X-chromosome inactivation in six females with heterozygous pathogenic DNAAF6 variants, 54.3%±10 (range 38%-70%) of multiciliated cells were defective. Nevertheless, in vitro and in vivo assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms. CONCLUSIONS: Our findings indicate that 30%-62% of functioning multiciliated respiratory cells are able to generate either normal or slightly reduced ciliary clearance. Because heterozygous females displayed either no or subtle respiratory symptoms, complete correction of 30% of cells by precision medicine might be able to improve ciliary airway clearance in PCD individuals as well as clinical symptoms.
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Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene.
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Hidronefrosis , Ratones Transgénicos , Fenotipo , Animales , Hidronefrosis/genética , Ratones , Tetraspaninas/genética , Tetraspaninas/metabolismo , Ornitina Carbamoiltransferasa/genética , Ornitina Carbamoiltransferasa/metabolismo , Hígado/metabolismo , Hígado/patología , Modelos Animales de Enfermedad , Riñón/patología , Riñón/metabolismo , MasculinoRESUMEN
Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune disease that can affect multiple organs. While the exact disease etiology remains incompletely understood, there is a suggested influence of X-chromosome dosage in the pathogenesis of lupus. Here, we report a rare case of a female patient diagnosed with mosaic Turner syndrome and subsequently presenting with juvenile-onset SLE. DNA methylation patterns were analyzed in this patient and compared with age-matched female SLE controls, revealing higher methylation levels in interferon-regulated genes previously shown to be hypomethylated in SLE. These data provide a potential link between a gene-dose effect from the X-chromosome and the lupus-defining epigenotype. We hypothesize that the attenuated demethylation in interferon-regulated genes might provide a protective effect explaining the rarity of SLE in Turner syndrome.
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Metilación de ADN , Lupus Eritematoso Sistémico , Síndrome de Turner , Femenino , Humanos , Cromosomas Humanos X/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/complicaciones , Síndrome de Turner/genética , Síndrome de Turner/complicaciones , NiñoRESUMEN
Several X-linked genes escape from X chromosome inactivation (XCI), while differences in escape across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA sequencing (scRNA-seq) data. The scLinaX and differentially expressed gene analyses with large-scale blood scRNA-seq datasets consistently identified the stronger escape in lymphocytes than in myeloid cells. An extension of scLinaX to a 10x multiome dataset (scLinaX-multi) suggested a stronger escape in lymphocytes than in myeloid cells at the chromatin-accessibility level. The scLinaX analysis of human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes suggested the underlying impact of escape on the genotype-phenotype association. Overall, scLinaX and the quantified escape catalog identified the heterogeneity of escape across cell types and tissues.
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Análisis de la Célula Individual , Inactivación del Cromosoma X , Inactivación del Cromosoma X/genética , Humanos , Análisis de la Célula Individual/métodos , Femenino , Linfocitos/metabolismo , Masculino , Estudio de Asociación del Genoma Completo , Animales , Células Mieloides/metabolismo , Ratones , Análisis de Secuencia de ARN/métodos , Especificidad de Órganos , Genes Ligados a X/genéticaRESUMEN
INTRODUCTION: Lung cancer is the most common cancer worldwide in mortality and the second in incidence. Epidemiological studies found a higher lung cancer risk for smoking women in comparison to men, but these sex differences, irrespective of smoking habits, remain controversial. One of the hypotheses concerns the genetic contribution of the sex chromosomes. However, while genome-wide association studies identified many lung cancer susceptibility loci, these analyses have excluded X-linked loci. METHODS: To account for nongenetic factors, we first presented an association test based on an additive-multiplicative hazard model accounting for random/nonrandom X-inactivation process. A simulation study was performed to investigate the properties of the proposed test as compared with the Wald test from a Cox model with random X-inactivation process and the partial likelihood ratio test proposed by Xu et al. accounting for nonrandom X-inactivation process. Then, we performed an X chromosome-wide association study on 9,261 individuals from the population-based cohort CARTaGENE to identify susceptibility loci for lung cancer among current and past smokers. We adjusted for the PLCOm2012 lung cancer risk score used in screening programs. RESULTS: Simulation results show the good behavior of the proposed test in terms of power and type I error probability as compared to the Xu et al. and the Wald test. Using the proposed test statistic and adjusting for the PLCOm2012 score, the X chromosome-wide statistical analysis identified two SNPs in low-linkage disequilibrium located in the IL1RAPL1 (IL-1 R accessory protein-like) gene: rs12558491 (p = 2.75×10-9) and rs12835699 (p = 1.26×10-6). For both SNPs, the minor allele was associated with lower lung cancer risk. Adjusting for multiple testing, no signal was detected using the Wald or the Xu et al. likelihood ratio tests. CONCLUSION: By taking into account smoking behavior and the X-inactivation process, the investigation of the X chromosome has shed a new light on the association between X-linked loci and lung cancer. We identified two loci associated with lung cancer located in the IL1RAPL1 gene. This finding would have been overlooked by examining only results from other test statistics.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares , Inactivación del Cromosoma X , Humanos , Neoplasias Pulmonares/genética , Femenino , Masculino , Fumar/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Fumadores , Cromosomas Humanos X/genética , Sitios Genéticos , Anciano , Simulación por ComputadorRESUMEN
BACKGROUND: Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. RESULTS: XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. CONCLUSIONS: We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome's role in regulating gene expression and sex differences in humans.
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Cromosomas Humanos X , Células Madre Pluripotentes Inducidas , ARN Largo no Codificante , Inactivación del Cromosoma X , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Femenino , Cromosomas Humanos X/genética , Masculino , ARN Largo no Codificante/genética , Alelos , Regulación de la Expresión Génica , Metilación de ADNRESUMEN
Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.
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The tree shrew (Tupaia belangeri) is a promising emerging model organism in biomedical studies, notably due to their evolutionary proximity to primates. To enhance our understanding of how DNA methylation is implicated in regulation of gene expression and the X chromosome inactivation (XCI) in tree shrew brains, here we present their first genome-wide, single-base-resolution methylomes integrated with transcriptomes from prefrontal cortices. We discovered both divergent and conserved features of tree shrew DNA methylation compared to that of other mammals. DNA methylation levels of promoter and gene body regions are negatively correlated with gene expression, consistent with patterns in other mammalian brains studied. Comparing DNA methylation patterns of the female and male X chromosomes, we observed a clear and significant global reduction (hypomethylation) of DNA methylation across the entire X chromosome in females. Our data suggests that the female X hypomethylation does not directly contribute to the gene silencing of the inactivated X chromosome nor does it significantly drive sex-specific gene expression of tree shrews. However, we identified a putative regulatory region in the 5' end of the X inactive specific transcript (Xist) gene, a key gene for XCI, whose pattern of differential DNA methylation strongly relate to its differential expression between male and female tree shrews. We show that differential methylation of this region is conserved across different species. Moreover, we provide evidence suggesting that the observed difference between human and tree shrew X-linked promoter methylation is associated with the difference in genomic CpG contents. Our study offers novel information on genomic DNA methylation of tree shrews, as well as insights into the evolution of X chromosome regulation in mammals.