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Female Mice with an Xist Deletion in B Cells Can Develop Lupus-Associated Phenotypes

ABSTRACT: Systemic lupus erythematosus (SLE) is a female-biased autoimmune disease. X-Chromosome Inactivation (XCI) dosage compensates X-linked genes in females. Disrupted localization of Xist, a critical regulator of XCI, and aberrant expression of X-linked genes in female SLE patients and SLE mouse models suggest that XCI impairment contributes to disease. To test this, we conditionally deleted Xist in B cells (Xist cKO mice). Remarkably, some female Xist cKO mice spontaneously develop SLE phenotypes, including expansion of activated B cell subsets, development of disease-associated autoantibodies, and glomerulonephritis. Moreover, female Xist cKO mice with chemically induced SLE developed more activated B cells and dsDNA autoantibodies compared to treated wildtype female mice. Activated B cells from Xist cKO mice with SLE phenotypes have increased expression of X-linked immunity genes implicated in female-biased SLE. Our findings demonstrate that perturbations in B cell XCI maintenance directly contribute to female-biased SLE via upregulation of X-linked immunity-related genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE266231 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism in female cells to regulate X-linked gene expression. We report here that subcultures from established lines of female hESCs displayed variations (0-100%) in the expression of XCI markers such as XIST RNA coating and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on inactive X chromosome. Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a mono-allelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already non-random. However, XIST gene expression in subsets of female hESCs is unstable and subject to epigenetic silencing through DNA methylation. Concomitant with the loss of XCI markers including XIST expression and H3K27me3, approximately 12% of X-linked CpG islands become hypomethylated and a subset of previously silenced X-linked alleles are reactivated, resulting a significant elevation of gene expression dosage. Because changes in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine. Keywords: Genotyping, gene expression and DNA methylation We used Affymetrix Genotyping array for looking for X-linked SNPs with HSF6, H7 and H9 genomic DNA, Agilent Gene expression array for comparing gene expression patten changes between HSF6 hESCs with X-inactiation and HSF6 hESCs without X-inactivation (3 repeats). Finally, mDIP-Chip method was used to detect X-linked CpG island methylation changes differences between hESCs with X-inactivation and hESCs without X-inactivation using Agilent CpG island array (3 repeats, and one of them has dye swap)

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Female Mice with an Xist Deletion in B Cells Can Develop Lupus-Associated Phenotypes

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