Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

@article{Odhams2019InterferonIX,
  title={Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus},
  author={Christopher A. Odhams and Amy L. Roberts and Susan K. Vester and Carolina S. T. Duarte and Charlie T Beales and Alexander J. Clarke and Sonja Lindinger and Samuel J Daffern and Antonino Zito and Lingyan Chen and Leonard L. Jones and Lora Boteva and David L. Morris and Kerrin S. Small and Michelle M. A. Fernando and Deborah S Cunninghame Graham and Timothy J. Vyse},
  journal={Nature Communications},
  year={2019},
  volume={10}
}
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in… 

Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis

CXorf21 is more highly expressed in female compared to male cells and is involved in a sexually dimorphic response to TLR7 activation, which skews cellular immune responses in manner consistent with expected properties of a mediator of the X chromosome dose risk in SLE and pSS.

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells are reviewed.

The role of TASL in the pathogenesis of SLE: X marks the spot

These findings are relevant to the pathogenesis of SLE since, in this disease, DNA and RNA in the form of immune complexes can enter cells of the innate immune system to induce responses by TLR 7, 8 and 9 in the endosomes; the production of interferon and other proinflammatory cytokines is an outcome of this pathway.

Type I IFN-dependent antibody response at the basis of sex dimorphism in the outcome of COVID-19

X marks the spot in autoimmunity

An overview on the role of chromosome X (chrX) in explaining why females have higher susceptibility to autoimmunity is provided and some essential concepts regarding chrX inactivation, escape from chr X inactivation and the evolutionary history are outlined.

B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells

It is shown XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7, and cell-type-specific diversification of lncRNA-protein complexes increase lnc RNA functionalities, and expand roles for XIST in sex-differences in biology and medicine.

X-factors in human disease: Impact of gene content and dosage regulation.

This review focuses on the peculiarities of the X chromosome genetic content and epigenetic regulation in shaping the manifestation of congenital and acquired X-linked disorders in a sex-specific manner.
...

References

SHOWING 1-10 OF 80 REFERENCES

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

This study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new genome-wide association study, a meta-analysis with a published GWAS and a replication study, which mapped 43 susceptibility loci, including ten new associations.

Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression

This work mapped interindividual variation in gene expression as a quantitative trait, defining expression quantitative trait loci (eQTLs) and found trans associations to the major histocompatibility complex are dependent on context, paralleling the expression of class II genes.

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X

The inactive X is predisposed to become partially reactivated in mammalian female lymphocytes, resulting in the overexpression of immunity-related genes in females, providing the first mechanistic evidence to the authors' knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.

Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants

A fine-mapping algorithm is developed to identify candidate causal variants for 21 autoimmune diseases from genotyping data, and it is found that most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap

This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in Sle, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

THE X-FILES OF INFLAMMATION: CELLULAR MOSAICISM OF X-LINKED POLYMORPHIC GENES AND THE FEMALE ADVANTAGE IN THE HOST RESPONSE TO INJURY AND INFECTION

It is argued that the sex benefit of females during the host response is associated with polymorphism of X- linked genes and cellular mosaicism for X-linked parental alleles, which represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response.

Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus

It is concluded that to better understand the true functional consequence of regulatory variants, quantification by RNA‐Seq should be performed at the exon‐level as a minimum, and run in parallel with gene and splice‐junction level quantification.

X-inactivation profile reveals extensive variability in X-linked gene expression in females

A comprehensive X-inactivation profile of the human X chromosome is presented, representing an estimated 95% of assayable genes in fibroblast-based test systems, and suggests a remarkable and previously unsuspected degree of expression heterogeneity among females.

Recapitulation of Candidate Systemic Lupus Erythematosus-Associated Variants in Koreans

The data support that FCGR polymorphisms play important roles in the susceptibility to SLE in diverse populations, including Koreans, and indicate that genome-wide association studies have identified novel single-nucleotide polymorphisms associated with the risk of SLE across diverse populations.

Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci

umerous looping interactions are reported and evidence that only a minority of interactions are common to both B- and T-cell lines is provided, suggesting interactions may be highly cell-type specific.
...