Dataset Information

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

ABSTRACT: Immune responses differ between women and men, and type I interferon (IFN) responses following Toll-like receptor 7 (TLR7) stimulation are higher in women. The precise mechanisms driving these sex differences in immunity are unknown. To investigate possible genetic factors, we quantify escape from X chromosome inactivation (XCI) for TLR7 and four other genes (RPS6KA3, CYBB, BTK, and IL13RA1) at the single plasmacytoid dendritic cell (pDC) level. We observe escape from XCI for all investigated genes, leading to biallelic expression patterns. pDCs with biallelic gene expression have significantly higher mRNA levels of the respective genes. Unstimulated pDCs with biallelic TLR7 expression exhibit significantly higher IFN?/? mRNA levels, and IFN? exposure results in significantly increased IFN?/? protein production by pDCs. These results identify unanticipated heterogeneity in escape from XCI of several genes in pDCs and highlight the important contribution of X chromosome factors to sex differences in type I IFN responses, which might explain observed sex differences in human diseases.

SUBMITTER: Hagen SH

PROVIDER: S-EPMC7833293 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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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.

Hagen Sven Hendrik SH Henseling Florian F Hennesen Jana J Savel Hélène H Delahaye Solenne S Richert Laura L Ziegler Susanne Maria SM Altfeld Marcus M

Cell reports 20201201 10

Immune responses differ between women and men, and type I interferon (IFN) responses following Toll-like receptor 7 (TLR7) stimulation are higher in women. The precise mechanisms driving these sex differences in immunity are unknown. To investigate possible genetic factors, we quantify escape from X chromosome inactivation (XCI) for TLR7 and four other genes (RPS6KA3, CYBB, BTK, and IL13RA1) at the single plasmacytoid dendritic cell (pDC) level. We observe escape from XCI for all investigated ge ...[more]

PMID: 33296655

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Project description:Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored. Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a platform for culture of sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-seq was used to define pathways likely to be involved in driving sex-dependent activation. Interventions using small molecule inhibitors were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, α-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways, and transcriptome analyses and small molecule interventions implicate genes that escape X-chromosome inactivation in regulating sex differences in AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.

Dataset Information

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

Publications

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

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