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X-linked transcriptome dysregulation across immune cells in systemic lupus erythematosus

2025-09-25Artigo científico Acesso aberto
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dc.contributor.authorSoares, Mafalda
dc.contributor.authorWemans, Inês Saraiva
dc.contributor.authorCaldas, Paulo
dc.contributor.authorda Rocha, Simão Teixeira
dc.contributor.authorGrosso, Ana Rita
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.institutionDCV - Departamento de Ciências da Vida
dc.contributor.pblBioMed Central (BMC)
dc.date.accessioned2026-01-22T09:54:01Z
dc.date.available2026-01-22T09:54:01Z
dc.date.issued2025-09-25
dc.descriptionPublisher Copyright: © The Author(s) 2025.
dc.description.abstractBACKGROUND: Systemic lupus erythematosus (SLE) is a complex immune-mediated disease with a strong female predominance. This sex bias may be linked to the presence of two X chromosomes, which are not always adequately dosage compensated by X chromosome inactivation (XCI). Disruption in X-linked transcriptome expression may contribute to altered immune function and increased susceptibility to autoimmunity.METHODS: To investigate the role of X-linked gene expression in SLE, we performed a comprehensive transcriptome analysis of 27 immune cell types from 125 female SLE patients and 66 healthy controls. We further applied a multivariate approach to integrate X-linked gene expression across all immune cell types and classify SLE patients. Additionally, we extended these models to other chromosomes and explored the correlation between autosome disease markers, including members of the XIST-interactome, and X-linked expression.RESULTS: We observed a significant increase in X-linked gene expression in T cells, B cells and plasmablasts, while monocytes and plasmacytoid dendritic cells exhibited the opposite trend. Multivariate models based solely on X-linked expression were highly accurate and highlighted key disease-associated markers. Interestingly, autosome-based models relied on markers highly correlated with X-linked gene expression and components of the XIST-interactome, which regulates XCI. Notably, we found that XIST lncRNA was consistently downregulated across multiple cell types, particularly in monocytes and Th1 cells. Such downregulation correlated with increased expression of SLE-associated genes, interferon signalling, and epigenetic regulators like KMT2D. Further analysis revealed extensive dysregulation of the XIST-interactome in SLE, predicting X-linked transcriptome alterations in a cell-type-specific manner.CONCLUSIONS: Here, we present a comprehensive analysis of X-linked gene expression across immune cells in SLE. Our study highlights the complexity of X-linked transcriptional changes, with distinct patterns observed across both innate and adaptive immune cell types. These findings offer novel insights into the role of the X-transcriptome in sex-biased autoimmune susceptibility and may support future efforts to identify molecular targets relevant to SLE pathogenesis.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent17
dc.format.extent6995809
dc.identifier.doi10.1186/s13293-025-00750-3
dc.identifier.issn2042-6410
dc.identifier.otherPURE: 149264048
dc.identifier.otherPURE UUID: 50bc8d9f-a32c-4005-9fd1-1f701ffceedb
dc.identifier.otherPubMed: 40999523
dc.identifier.otherPubMedCentral: PMC12466074
dc.identifier.otherScopus: 105017185864
dc.identifier.otherWOS: 001578761500001
dc.identifier.otherORCID: /0000-0001-6974-4209/work/203333395
dc.identifier.urihttp://hdl.handle.net/10362/199625
dc.identifier.urlhttps://www.scopus.com/pages/publications/105017185864
dc.identifier.urlhttps://www.webofscience.com/wos/woscc/full-record/WOS:001578761500001
dc.language.isoeng
dc.peerreviewedyes
dc.subjectHumans
dc.subjectLupus Erythematosus, Systemic/genetics
dc.subjectFemale
dc.subjectTranscriptome
dc.subjectGenes, X-Linked
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectX Chromosome Inactivation
dc.subjectChromosomes, Human, X
dc.subjectRNA, Long Noncoding/genetics
dc.subjectMale
dc.subjectGender Studies
dc.subjectEndocrinology
dc.titleX-linked transcriptome dysregulation across immune cells in systemic lupus erythematosusen
dc.typejournal article
degois.publication.firstPage1
degois.publication.lastPage17
degois.publication.titleBiology of sex differences
degois.publication.volume16
dspace.entity.typePublication
rcaap.rightsopenAccess

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