Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

Hagen, Sven; Henseling, Florian; Hennesen, Jana; Savel, Hélène; Delahaye, Solenne; Richert, Laura; Ziegler, Susanne; Altfeld, Marcus

doi:10.1016/j.celrep.2020.108485

Cited by 90 publications

(93 citation statements)

References 68 publications

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“…This molecular mechanism might also provide a plausible explanation for the higher COVID-19 mortality rates among males compared to females [287,288]. The above data suggest that female pDCs with biallelic TLR7 expression respond more rapidly to SARS-CoV-2 infection by producing large amounts of type IFNs that might account for the better control of SARS-CoV-2 infection in women compared to men [286]. This idea is also supported by a recent report showing that loss-of-function mutation of X-chromosomal TLR7 is associated with impaired type I IFN responses of young male patients with severe COVID-19 that further emphasizes the importance of intact TLR7-mediated type I IFN responses in the pathogenesis of the disease [289].…”

Section: Discussionmentioning

confidence: 84%

“…Indeed, single cell analyses of TLR7 allelic expression in pDCs, B cells and monocytes from females and Klinefelter (XXY) individuals revealed that TLR7 escapes from X chromosome silencing. A recent study further demonstrated that female pDCs with biallelic TLR7 expression have higher type I IFN production than monoallelic TLR7 expressing pDCs, presumably due to the IFNAR mediated type I IFN positive feedback loop [286]. This molecular mechanism might also provide a plausible explanation for the higher COVID-19 mortality rates among males compared to females [287,288].…”

Section: Discussionmentioning

confidence: 96%

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Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

Bencze

Fekete

Pázmándi

2021

IJMS

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One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

Bencze

Fekete

Pázmándi

2021

IJMS

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“…Single-cell RNA-sequencing (RNA-seq) has also been used to avoid the need for clonal cell populations when using Xi/Xa expression to make XCI status calls [ 19 ]. Single-cell RNA-seq can additionally see variation in XCI status between different Xi alleles within the same sample and heterogeneity has even been observed in XCI status of a gene in cells with the same Xi [ 6 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation

Balaton

Brown

2021

Epigenetics & Chromatin

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Background X-chromosome inactivation (XCI) is the epigenetic inactivation of one of two X chromosomes in XX eutherian mammals. The inactive X chromosome is the result of multiple silencing pathways that act in concert to deposit chromatin changes, including DNA methylation and histone modifications. Yet over 15% of genes escape or variably escape from inactivation and continue to be expressed from the otherwise inactive X chromosome. To the extent that they have been studied, epigenetic marks correlate with this expression. Results Using publicly available data, we compared XCI status calls with DNA methylation, H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3 and H3K36me3. At genes subject to XCI we found heterochromatic marks enriched, and euchromatic marks depleted on the inactive X when compared to the active X. Genes escaping XCI were more similar between the active and inactive X. Using sample-specific XCI status calls, we found some marks differed significantly with variable XCI status, but which marks were significant was not consistent between genes. A model trained to predict XCI status from these epigenetic marks obtained over 75% accuracy for genes escaping and over 90% for genes subject to XCI. This model made novel XCI status calls for genes without allelic differences or CpG islands required for other methods. Examining these calls across a domain of variably escaping genes, we saw XCI status vary across individual genes rather than at the domain level. Lastly, we compared XCI status calls to genetic polymorphisms, finding multiple loci associated with XCI status changes at variably escaping genes, but none individually sufficient to induce an XCI status change. Conclusion The control of expression from the inactive X chromosome is multifaceted, but ultimately regulated at the individual gene level with detectable but limited impact of distant polymorphisms. On the inactive X, at silenced genes euchromatic marks are depleted while heterochromatic marks are enriched. Genes escaping inactivation show a less significant enrichment of heterochromatic marks and depletion of H3K27ac. Combining all examined marks improved XCI status prediction, particularly for genes without CpG islands or polymorphisms, as no single feature is a consistent feature of silenced or expressed genes.

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“…The four core genotype mouse model enables the study of differences in gene expression solely due to sex chromosome complement without involvement of sex hormones (86). Such an approach is useful to assess the role of IL-1 receptor-associated kinase-1 (IRAK1), CD40 ligand (CD40LG), C-X-C motif chemokine receptor 3, and IL13RA1 or TLR7 genes known to escape the X-related inactivation process in infectious diseases (6,(87)(88)(89). These findings highlight enhanced female immune response to infectious agents through the involvement of X-chromosome-linked genes.…”

Section: Genetic Factors and Sexual Dimorphismmentioning

confidence: 99%

Sexual Dimorphism and Gender in Infectious Diseases

et al. 2021

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Epidemiological studies and clinical observations show evidence of sexual dimorphism in infectious diseases. Women are at less risk than men when it comes to developing most infectious diseases. However, understanding these observations requires a gender approach that takes into account an analysis of both biological and social factors. The host’s response to infection differs in males and females because sex differences have an impact on hormonal and chromosomal control of immunity. Estradiol appears to confer protective immunity, while progesterone and testosterone suppress anti-infectious responses. In addition, genetic factors, including those associated with sex chromosomes, also affect susceptibility to infections. Finally, differences in occupational activities, lifestyle, and comorbidities play major roles in exposure to pathogens and management of diseases. Hence, considering sexual dimorphism as a critical variable for infectious diseases should be one of the steps taken toward developing personalized therapeutic approaches.

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Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

Abstract: Highlights d TLR7, CYBB, RPS6KA3, BTK, and IL13RA1 can escape XCI in human pDCs d Female pDCs with escape from XCI have higher mRNA levels of the respective genes d pDCs with escape from XCI of TLR7 have higher IFNa/b mRNA levels

Cited by 90 publications

References 68 publications

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation

Sexual Dimorphism and Gender in Infectious Diseases

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