Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.
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We thank A.A. Dlugosz for critical discussions and reading of the manuscript; S. Stoll, Y. Xu, T. Quan, Y. Li, L. Wolterink and L. Reingold for technical help; and A. Libs for help with biopsy samples and files. Supported by the US National Institutes of Health (K08-AR060802 and R01-AR069071to J.E.G.; and R03-AR066337 and K08-AR063668 to J.M.K.), an A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (J.E.G.), the Doris Duke Charitable Foundation (2013106 to J.E.G.) and a Pfizer Aspire Award (J.E.G.).
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Integrated supplementary information
a, pie chart of the percentage of genes that underwent and escaped X inactivation in female human skins. b-d, examples of the expression of escapees with Y orthologues in females and males. e-g, examples of the expression of escapees without Y orthologues in females and males. Mean+stdev, * P<0.05. Student’s t-test.
a, genome-wide gender-differences in expression correlation for female-biased genes. b, correlation between gene-gene spearman correlations estimated from RNA-seq samples (columns) versus those estimated from microarray data (rows). *, significant correlation.
a, top functions enriched in female-biased genes. b, SLE/Systemic sclerosis and the atopic dermatitis loci are enriched with female-bias genes. c, the null distribution for the expected overlap for random loci, with red lines illustrating the observed overlap results from the SLE/SS (top) and AD (bottom), respectively. d, qRT-PCR analyses of female-biased immune genes in T cells extracted from blood of healthy humans (n=9 each sex). F, female. M, male. Mean ± s.e.m, * P<0.05. Student’s t-test. e-i, scatter plot of gene expression levels from RNA-Seq of human skin biopsies versus age at biopsy for ITGAM, C3, CFB, DOCK2, and FCER1G.
a-e, qRT-PCR analyses of VGLL3, UTX, ZFX, FEZ, FHL upon their knockdown by RNAi (n=3). f, qRT-PCR analyses of UTX and ZFX upon VGLL3 knockdown (n=3). Mean ± s.e.m, * P<0.05. Student’s t-test.
a, cis-eQTL signal at chr3:87902673 (p=4e-05) around VGLL3. b, significant eQTL results for chr3:87902673 against different expression traits. c, Top pathways regulated by VGLL3.
a, log2(FC) of autoimmune disease genes upon VGLL3 RNAi. b, density plot of log2(FC) levels upon VGLL3 knockdown for plaque psoriasis (PP) and non-PP genes. c, density plot of log2(FC) levels upon VGLL3 knockdown for SCLE and PP genes. d, density plot of log2(FC) levels upon Fez knockdown for SCLE and non-SCLE genes. e, density plot of log2(FC) levels upon Fyn knockdown for SCLE and non-SCLE genes. b-e, Wilcoxon-Matt-Whitney test. f, gene expression levels in female (F) and male (M) SCLE patients by RNA-Seq. Mean+s.e.m. g, associations of VGLL3 targets with various autoimmune conditions, with (*) indicating the observed mean of VGLL3 target gene expression and box indicating 1st and 3rd percentile for the null distribution for the mean signed log10 P-value (2000 simulations). h, expression of VGLL3 targets and non-targets in Sjögren’s syndrome, showing higher percentage of Vgll3 targets that have increased expression in disease (red boxed region) compared to non-targets (grey boxed region). Mann-Whitney U test.
Supplementary Figures 1–6 (PDF 981 kb)
Lists of gender biased genes (XLSX 50 kb)
Details for TF screening for regulation of gender biased genes. (XLSX 35 kb)
VGLL3-regulated genes in keratinocytes (XLSX 58 kb)
Overlap between VGLL3-regulated genes and lupus-upregulated genes (XLSX 57 kb)
Lists of SCLE- and psoriasis-altered genes (XLSX 72 kb)
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Liang, Y., Tsoi, L., Xing, X. et al. A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat Immunol 18, 152–160 (2017). https://doi.org/10.1038/ni.3643
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