X-Chromosome Inactivation and Escape from X Inactivation in Mouse

Ma, Wenxiu; Bonora, Giancarlo; Berletch, Joel B.; Deng, Xinxian; Noble, William Stafford

doi:10.1007/978-1-4939-8766-5_15

Cited by 7 publications

(7 citation statements)

References 42 publications

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“…9 Mounting evidence indicates that this assumption is flawed, and we are only beginning to understand how escape from X inactivation affects female gene expression in different tissues and physiological contexts, including the cardiovascular system. [10][11][12] For example, incomplete X-chromosome inactivation has been implicated in sex-biased expression of endothelial inflammatory genes in women with HF with preserved ejection fraction (HFpEF). 13…”

Section: Biomarkers As Predictors Of Cvd: Why and How Does Sex Matter?mentioning

confidence: 99%

Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications

Lau

Binek

Parker

et al. 2022

Circulation Research

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Sex-based differences in cardiovascular disease presentation, diagnosis, and response to therapies are well established, but mechanistic understanding and translation to clinical applications are limited. Blood-based biomarkers have become an important tool for interrogating biologic pathways. Understanding sexual dimorphism in the relationship between biomarkers and cardiovascular disease will enhance our insights into cardiovascular disease pathogenesis in women, with potential to translate to improved individualized care for men and women with or at risk for cardiovascular disease. In this review, we examine how biologic sex associates with differential levels of blood-based biomarkers and influences the effect of biomarkers on disease outcomes. We further summarize key differences in blood-based cardiovascular biomarkers along central biologic pathways, including myocardial stretch/injury, inflammation, adipose tissue metabolism, and fibrosis pathways in men versus women. Finally, we present recommendations for leveraging our current knowledge of sex differences in blood-based biomarkers for future research and clinical innovation.

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Section: Biomarkers As Predictors Of Cvd: Why and How Does Sex Matter?mentioning

confidence: 99%

Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications

Lau

Binek

Parker

et al. 2022

Circulation Research

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“…However, it could be a way forward, for instance in identifying the genetic make-up of female patients who experience severe COVID-19. Various methods are available to study XCI escape ( 43 , 125 ). RNA sequencing (RNAseq) and expression data to identify XCI escape relies on good methods to differentiate alleles, usually SNP frequencies to distinguish alleles at multiple loci.…”

Section: Discussionmentioning

confidence: 99%

“…XCI escape can be studied in various ways, such as bulk RNA-sequencing (RNA-seq) to assess differential allelic expression or RNA fluorescence in situ hybridization (RNA FISH) to detect nascent RNA transcripts. XCI status can also be examined indirectly via epigenetic markers such as methylation patterns ( 43 ).…”

Section: Subsectionsmentioning

confidence: 99%

“…XCI takes place in the fetus, but it remains unclear when XCI escape takes place. Patterns of XCI escape have been observed already in trophoblastic cells, but in the embryo proper, where XCI escape is probably still absent ( 43 ). Initial XCI research already suggested inactivation state may be dynamic over the course of life ( 79 ), and later studies suggest that XCI gene silencing may indeed be variable and gene- and tissue specific ( 41 ).…”

Section: Subsectionsmentioning

confidence: 99%

“…Such studies have not been conducted with human cells in vitro nor in vivo . It would certainly be interesting to examine possible differences in XCI status in the course of female life, for TLR7 and other genes alike ( 43 , 81 ).…”

Section: Subsectionsmentioning

confidence: 99%

See 2 more Smart Citations

Why Females Do Better: The X Chromosomal TLR7 Gene-Dose Effect in COVID-19

Spiering

Vries

2021

Front. Immunol.

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A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.

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Sex Differences in Doxorubicin‐Induced Cardiotoxicity: Insights from Transcriptome Analysis

Su,

Fu,

Xiao

et al. 2024

Advanced Therapeutics

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Male patients have a higher risk of cardiotoxicity following doxorubicin (DOX) treatment than female patients. However, how this difference occurs at the transcriptome level remains unclear, and the mechanisms underlying these differences are understudied. This study aimed to describe the transcriptional patterns of males and females after DOX treatment and explore the possible mechanisms of sexual differences in DOX‐induced cardiotoxicity. Following DOX treatment, male mice exhibit more severe heart damage than female mice. Transcriptome analysis of mice with and without DOX treatment showed that differentially expressed genes (DEGs) are significantly different between males and females. The majority of DEGs are sex‐specific, and more DEGs are identified in males than females. A number of genes, including the oxidation‐related genes Gdf15 and Rbm3, exhibited altered expression either in males or females. Some other genes, including the ferroptosis‐related gene Cd74, changed their expression levels in both sexes, but at different scales. Biochemical experiments suggested that cardiomyocyte oxidation and ferroptosis may contribute to the sexual dimorphism of DOX‐induced cardiotoxicity. In summary, this study shows that, after exposure to DOX, males and females respond differently regarding the expression of hundreds of genes, including Gdf15, Rbm3, and Cd74, possibly explaining the sexual differences in DOX‐induced cardiotoxicity.

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X-Chromosome Inactivation and Escape from X Inactivation in Mouse

Cited by 7 publications

References 42 publications

Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications

Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications

Why Females Do Better: The X Chromosomal TLR7 Gene-Dose Effect in COVID-19

Sex Differences in Doxorubicin‐Induced Cardiotoxicity: Insights from Transcriptome Analysis

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