title: Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.
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.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jianle
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Camille M
authors.initials: CM
authors.lastname: Syrett
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Kramer
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Arindam
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Atchison
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; anguera@vet.upenn.edu.
authors.forename: Montserrat C
authors.initials: MC
authors.lastname: Anguera
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007109:Immunity / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D049951:X Chromosome Inactivation
chemical_list: D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C077885:XIST non-coding RNA
keywords: X chromosome inactivation; XIST RNA; epigenetics; female-biased autoimmunity