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ERRBS-Seq of XpYx and XmYx murine CD4+ T cells

ABSTRACT: Most autoimmune diseases have a higher incidence in women than men due to differences in sex hormones, sex chromosomes, or both. Female (XX) and male (XY) sex chromosome complements differ in parent-of-origin of the X chromosome, with females inheriting one each from the mother and father, while males inherit only one from the mother2. Here, we discovered that the paternal X (Xp) had higher DNA methylation than the maternal X (Xm) in autoantigen specific CD4+ T lymphocytes, potentially suppressing X gene expression in XX. Using the “Four Core Genotypes” model, the transcriptomes of autoantigen specific CD4+ T lymphocytes showed higher expression of many X genes in XY- than XX. Expression of toll-like receptor 7 (Tlr7) and forkhead box P3 (FoxP3), two X chromosome genes important in autoimmunity, was higher in XY- than XX, confirming genome wide methylation and transcription data. Thus, parent-of-origin differences in DNA methylation of X genes can lead to sexual dimorphisms in gene expression during autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE122787 | GEO | 2019/12/11

REPOSITORIES: GEO

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Project description:Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiome bacteria on humoral immune activation. Sham-operated and gonadectomized male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotypes. Ex vivo studies investigated the functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, in mitogenic B cell activation. We further evaluated whether gut microbiome communities, or their metabolites, differentially influence immune cell activation in a sex chromosome-dependent manner. Endogenous gut microbiomes were antibiotically depleted and reconstituted with select short-chain fatty acid (SCFA)-producing bacteria prior to HKSP immunization and immune responses assessed. XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria increased humoral responses in XX, but not XY, FCG mice. This XX-dependent enhancement appears to be independent of SCFA production in males, while female XX-dependent responses relied on SCFAs. FCG mice have been used to assess sex hormones and sex chromosome complements influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphisms.

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ERRBS-Seq of XpYx and XmYx murine CD4+ T cells

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ERRBS-Seq of XpYx and XmYx murine CD4+ T cells