ArticleProceedings of the National Academy of Sciences of the United States of America2016
Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 203 papers, 2 of them syntheses that pooled it.
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Who cites it
203 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- The role of microRNAs and long non-coding RNAs in epigenetic regulation of T cells: implications for autoimmunity.Frontiers in immunology · 2025Pooled it
- Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission.Nature communications · 2020Pooled it
- Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19.PLoS pathogens · 2021Trial
- Review
- Disease modification in lupus nephritis: towards a pathophysiology-based treatment paradigm.Nature reviews. Nephrology · 2026Review
- SPEN Loss Drives Extrafollicular Diffuse Large B-cell Lymphoma with Female-Specific Lethality and Therapeutic Vulnerabilities.Cancer discovery · 2026Article
- The why, what, who and when of B cell depletion in systemic lupus erythematosus: biological rationale, patient stratification and evolving therapeutic modalities.Rheumatology (Oxford, England) · 2026Review
- Escape from X-chromosome inactivation: from gene discovery to regulatory mechanisms.Biochemical Society transactions · 2026Review
- Single-cell analysis of fetal testis reveals dysfunction of human Leydig cells in Klinefelter syndrome.The Journal of clinical investigation · 2026Article
- Machine learning reveals X chromosome transcriptional signatures that classify systemic lupus erythematosus in females.BMC rheumatology · 2026Article
- Female mice with a Xist deletion in B cells can develop lupus-associated phenotypes.Cell reports · 2026Article
- Sex differences in response to longevity interventions.Ageing research reviews · 2026Review
- Why Is MS a More Frequent Complication of EBV Infection in Females?Immunological reviews · 2026Review
- Xist RNA dependent and independent mechanisms regulate dynamic X chromosome inactivation in B lymphocytes.Cell reports · 2026Article
- Sex matters: mechanistic insights into sex-driven patterns of autoimmunity and implications for pharmacotherapy.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- The X Factor in Immunity: Sex Differences Shaped by the X Chromosome.Immunological reviews · 2026Review
- The association between plant protein intake and cancer risk: a prospective cohort study.Nutrition journal · 2026Article
- Investigating Dysregulated X Chromosome Inactivation in Human B Cells and Plasmacytoid Dendritic Cells by RNA FISH.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Long noncoding RNA regulation of immunity.Nature immunology · 2026Review
- Xist in X chromosome inactivation: mechanisms and disease relevance.Cell communication and signaling : CCS · 2025Review
143 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors.
Funding
Abstract
Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.
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