The human inactive X chromosome modulates expression of the active X chromosome

Roman, Sabine; Godfrey, Alexander K.; Skaletsky,; Bellott,; Groff,; Blanton,; Hughes, Jennifer F.; Brown,; Phou,; Buscetta,; Kruszka,; Banks,; Dutra, Valéria; Pak, Abbas; Lasutschinkow,; Keen,; Davis, Shanlee; Tartaglia,; Samango-Sprouse,; Muenke,

doi:10.1101/2021.08.09.455676

Cited by 7 publications

(7 citation statements)

References 98 publications

(233 reference statements)

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“…Using RNA-seq and copy number data from the TARGET Data Matrix of the leukemia cohort of n = 123 samples, we found that each inactive X in a sporadic leukemia sample was contributing on average 24.6% of the level of expression of the active X to the overall expression of USP9X in B-ALL ( Figure 4 C), which is only slightly increased compared with 14% to 17% reported in lymphoblastoid cells and fibroblasts of patients with sex chromosomal aneuploidies. 46 The level of contribution from the inactive X for gene XIST in leukemia samples (n = 127) was 100% consistent with the previously reported germline analysis ( Figure 4 D). This analysis suggests that leukemia cells retain the same state of X inactivation as found in the germline and may explain why the leukemia samples with the highest USP9X expression derive from leukemia samples with extra copies of the X chromosome in female patients.…”

Section: Resultssupporting

confidence: 90%

“…Recent analysis performed on gene expression from X chromosomes in noncancer cells revealed that USP9X was expressed, albeit at a reduced level, from the inactive X. 46 We therefore aimed to determine whether leukemic bone marrow maintains a similar expression pattern for USP9X and other genes reported to be expressed by the inactive X. Using RNA-seq and copy number data from the TARGET Data Matrix of the leukemia cohort of n = 123 samples, we found that each inactive X in a sporadic leukemia sample was contributing on average 24.6% of the level of expression of the active X to the overall expression of USP9X in B-ALL ( Figure 4 C), which is only slightly increased compared with 14% to 17% reported in lymphoblastoid cells and fibroblasts of patients with sex chromosomal aneuploidies.…”

Section: Resultsmentioning

confidence: 99%

“… 4 However, a recent study used gene expression in normal lymphoblasts or fibroblasts from patients with sex chromosomal aneuploidy and demonstrated that for USP9X , each inactive X contributes only 14% to 17% of expression compared with the active X. 46 Using data from the TARGET phase 2 cohort of patients with sporadic ALL (n = 142 samples), which frequently demonstrate sex chromosome aneuploidy, we were able to demonstrate that leukemic cells retain the same pattern of expression from the inactive X as seen in nonmalignant samples.…”

Section: Discussionmentioning

confidence: 99%

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Identification of USP9X as a leukemia susceptibility gene

Sisoudiya

Mishra

et al. 2023

Blood Advances

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We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5kb de novo heterozygous in-frame deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n=42) demonstrated that MRXS99F probands with B-ALL (n=3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results (SEER) database (P<0.0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. Conversely, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females and expression levels are comparable in leukemia samples from both sexes (P=0.54) with the highest expressors being female patients with extra copies of X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes with low expression associated with poorer survival in high-risk B-ALL patients.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of USP9X as a leukemia susceptibility gene

Sisoudiya

Mishra

et al. 2023

Blood Advances

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“…In species pairs sharing an identical and chromosomal-level DC mechanism, this effect is expected to be relatively minor, since genes should not exhibit quantitative differences in the DC mechanism. However, in many species, many genes escape this global DC mechanism and exhibit gene-level expression control (85)(86)(87)(88)(89)(90)(91). These genes, if sufficiently numerous on the X could therefore also contribute to HR.…”

Section: The Overall Effect Of Strata 1 Andmentioning

confidence: 99%

A single theory for the evolution of sex chromosomes and the two rules of speciation

Lenormand,

Roze

2024

Preprint

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Three major empirical patterns involving sex chromosomes have been observed in higher eukaryotes: Y (or W) chromosomes are often non-recombining and degenerate; when two species hybridize, but one sex is sterile or inviable among hybrid offspring, it is most often the heterogametic sex (XY or ZW)-the so-called Haldane's rule; and the X (or Z) plays a disproportionately large effect on reproductive isolation compared to autosomes-the so-called large X effect. Each observation has generally received its own tailored explanation involving multiple genetic and evolutionary causes (1-3). Here, we show that these empirical patterns all emerge from a single theory incorporating the evolution of cis and trans-acting regulators of gene expression. This theory offers a level of parsimony and generality rarely seen in biology.

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“…DED1 is conserved in humans as DDX3X on the X-chromosome in females, and DDX3Y on the Y-chromosome in males. The DDX3X gene escapes X-linked inactivation and has two active alleles in most females [ 95 , 96 ]. Its male paralog, DDX3Y , shows lower and more variable expression in somatic tissues, as well as mosaic depletion with age in hematopoietic stem and progenitor cells through loss of Y [ 97 , 98 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the relationship between temperature and immunity

Maloney,

Duffy

2024

Discovery Immunology

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Fever is a hallmark symptom of disease across the animal kingdom. Yet despite the evidence linking temperature fluctuation and immune response, much remains to be discovered about the molecular mechanisms governing these interactions. In patients with rheumatoid arthritis for instance, it is clinically accepted that joint temperature can predict disease progression. But it was only recently demonstrated that the mitochondria of stimulated T cells can rise to an extreme 50°C, potentially indicating a cellular source of these localized “fevers”. A challenge to dissecting these mechanisms is bidirectional interplay between temperature and immunity. Heat shock response is found in virtually all organisms, activating protective pathways when cells are exposed to elevated temperatures. However, the temperature threshold that activates these pathways can vary within the same organism, with human immune cells in particular demonstrating differential sensitivity to heat. Such inter-cellular variation may be clinically relevant given the small but significant temperature differences seen between tissues, ages, and sexes. Greater understanding of how such small temperature perturbations mediate immune responses may provide new explanations for persistent questions in disease such as sex disparity in disease prevalence. Notably, the prevalence and severity of many maladies are rising with climate change, suggesting temperature fluctuations can interact with disease on multiple levels. As global temperatures are rising, and our body temperatures are falling, questions regarding temperature-immune interactions are increasingly critical. Here we review this aspect of environmental interplay to better understand temperature’s role in immune variation and subsequent risk of disease.

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The human inactive X chromosome modulates expression of the active X chromosome

Cited by 7 publications

References 98 publications

Identification of USP9X as a leukemia susceptibility gene

Identification of USP9X as a leukemia susceptibility gene

A single theory for the evolution of sex chromosomes and the two rules of speciation

Deciphering the relationship between temperature and immunity

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