An integrative approach to assess X‐chromosome inactivation using allele‐specific expression with applications to epithelial ovarian cancer

Larson, Nicholas B.; Fogarty, Zachary C.; Larson, Melissa C.; Kalli, Kimberly R.; Lawrenson, Kate; Gayther, Simon A.; Fridley, Brooke L.; Goode, Ellen L.; Winham, Stacey J.

doi:10.1002/gepi.22091

Cited by 19 publications

(30 citation statements)

References 50 publications

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“…Curiously, ARSD is active in adult tissues, but silenced in the placenta. Larson et al (2017) observed that ARSD is inactivated in at least one ovarian tumor sample, highlighting a potential parallel between the placenta and tumor development (Larson et al 2017). PRKX is also shown to be an escape gene in adult tissues here, and as previously reported (Wainer Katsir and Linial 2019), but not in the placenta.…”

Section: Discussionsupporting

confidence: 85%

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues

Phung

Olney

Silasi

et al. 2019

Preprint

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The placenta is formed after the first few weeks of pregnancy and is the genotype of the fetus. It acts as an immune modulator in the uterine environment to sustain a successful pregnancy.One of the X chromosomes in XX females is silenced by a process called X-inactivation. Prior research suggests that incorrect dosage on the X chromosome could lead to poor development of the placenta and ultimately result in complications in pregnancy. Previous studies of Xinactivation in the placenta were either in non-human placentas, or were limited to only a few SNPs and genes in human placentas. Thus, it is not clear whether within human placenta, Xinactivation is completely homogeneous, patchy, or mosaic. Further, X-inactivation is not complete in humans; as many as one-third of the genes on the X chromosome escape Xinactivation, but variability in genes that escape X-inactivation in the placenta has not been investigated. We sequenced RNA from 60 placenta samples from 30 full-term, uncomplicated pregnancies with female offspring. We can confidently rule out X-inactivation being completely mosaic in the human placenta. Rather, we find strong evidence that X-inactivation in the human placenta is patchy, with large potential clonal expansions of either silenced maternal or paternal X-chromosomes, with provocative suggestions of bias towards silencing the paternal X. We also find variation in the degree of silencing, where a high portion of variants (between 26.8-75.3% in any sample) are silenced incompletely. Finally, we find evidence for variability in genes that escape X-inactivation within and among placenta samples. SignificanceThe placenta is formed early during development, is essential for healthy pregnancy, and is largely composed of DNA from the offspring, and thus can be XX or XY. One of the X chromosomes in XX females is silenced by a process called X-inactivation. We studied patterns of X-inactivation in two regions of the placenta across 30 placentas, and find strong evidence for large patches of either maternally or paternally silenced X-chromosomes in the human placenta. We also found that the genes that escape X-inactivation vary both across individuals, and within the placenta of a single individual, suggesting mechanisms for variability in placenta function, and implications for prenatal testing that samples only a single region of the placenta.

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Section: Discussionsupporting

confidence: 85%

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues

Phung

Olney

Silasi

et al. 2019

Preprint

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“…The human Xi/Xa expression-based calls had 83% agreement with previous calls, with the discrepancies largely in genes variably escaping from XCI [15]. As cancer samples were used to allow Xi/Xa analysis, some epigenetic dysregulation may have occurred [20]. Our study was further limited by the need for heterozygous polymorphisms, thus with only 8 samples, any mis-regulation may not have been noticeable, or led to false or missed calls of variable escape from XCI.…”

Section: Discussionmentioning

confidence: 99%

“…For allelic expression to be used to examine XCI escape status, the samples analyzed must be skewed so that the majority of cells in the sample have the same Xi. Skewing of XCI >90% occurs infrequently in human, but at elevated incidence in blood [19] and cancer due to its monoclonal origin [20]. Cell lines that have undergone clonal selection or which are skewed due to X-linked diseases have also been used [14].…”

Section: Introductionmentioning

confidence: 99%

Cross-species examination of X-chromosome inactivation highlights domains of escape from silencing

Balaton

Fornés

Wasserman

et al. 2020

Preprint

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BackgroundX-chromosome inactivation (XCI) in eutherian mammals is the epigenetic inactivation of one of the two X chromosomes in XX females in order to compensate for dosage differences with XY males. Not all genes are inactivated, and the proportion escaping from inactivation varies between human and mouse (the two species that have been extensively studied).ResultsWe used DNA methylation to predict the XCI status of X-linked genes with CpG islands across 12 different species: human, chimp, bonobo, gorilla, orangutan, mouse, cow, sheep, goat, pig, horse and dog. We determined the XCI status of 342 CpG islands on average per species, with most species having 80-90% of genes subject to XCI. Mouse was an outlier, with a higher proportion of genes subject to XCI than found in other species. Sixteen genes were found to have discordant X-chromosome inactivation statuses across multiple species, with five of these showing primate-specific escape from XCI. These discordant genes tended to cluster together within the X chromosome, along with genes with similar patterns of escape from XCI. CTCF- binding, ATAC-seq signal and LTR repeats were enriched at genes escaping XCI when compared to genes subject to XCI; however, enrichment was only observed in three or four of the species tested. LINE and DNA repeats showed enrichment around subject genes, but again not in a consistent subset of species.ConclusionsIn this study we determined XCI status across 12 species, showing mouse to be an outlier with few genes that escape inactivation. Inactivation status is largely conserved across species. The clustering of genes that change XCI status across species implicates a domain-level control. In contrast, the relatively consistent, but not universal correlation of inactivation status with enrichment of repetitive elements or CTCF binding at promoters demonstrates gene-based influences on inactivation state. This study broadens enrichment analysis of regulatory elements to species beyond human and mouse.

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“…To investigate the relationship between age (age of sampling) and XCI pattern, all SCZ patients and age-matched CNTLs were subgrouped by age as children (age ≤ 18), adults (age [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and elderly individuals (age ≥ 50), as shown in Table 1. The MDD patients, who served as psychiatric disease controls for the SCZ patients, were also subgrouped by age as adults (age [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and elderly individuals (age ≥ 50). The SCZ and MDD patients were diagnosed by at least two experienced psychiatrists according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth or fifth edition (DSM-IV or DSM-V, respectively).…”

Section: Subjectsmentioning

confidence: 99%

“…The most common criterion for “skewed” XCI has been defined as XCI from the same allele in 75% or 80% of cells [ 24 – 26 ], while very skewed XCI is defined as 90% of cells with same-allele XCI [ 27 ]. While skewed XCI has been found to be associated with immune disease, thyroid disease and cancer [ 28 – 30 ], recent studies have found that the frequency of skewed XCI is related to aging, with even higher skewing in older patients with Alzheimer’s disease or Parkinson’s disease [ 27 , 31 ]. In psychiatric disease studies, X-linked intellectual disability has been reported in association with skewed XCI as well as X chromosome gene variants in these patients, for example, in MECP2 , DDX3X , SMC1A [ 5 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation

Zhang

et al. 2020

Biol Sex Differ

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Background: X chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with Xlinked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia. Methods: A total of 109 female schizophrenia (SCZ) patients and 80 age-and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups. Results: First, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the ageand sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers. Limitations: The XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease. Conclusion: Our study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.

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An integrative approach to assess X‐chromosome inactivation using allele‐specific expression with applications to epithelial ovarian cancer

Cited by 19 publications

References 50 publications

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues

Cross-species examination of X-chromosome inactivation highlights domains of escape from silencing

A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation

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