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A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases

Nature Immunology volume 18, pages 152–160 (2017)Cite this article

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Abstract

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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Figure 1: Identification of sex-biased genes from human skin biopsies.
Figure 2: Female-biased genes encode products associated with autoimmune processes.
Figure 3: Expression of female-biased genes encoding products related to immunity is dependent on SLE disease states but not on sex-hormone levels.
Figure 4: VGLL3 regulates genes associated with autoimmune diseases.
Figure 5: VGLL3 targets encode products involved in multiple autoimmune conditions.
Figure 6: VGLL3 regulation of genes altered in SS.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA

    Yun Liang, Lam C Tsoi, Xianying Xing, Maria A Beamer, William R Swindell, Mrinal K Sarkar, Philip E Stuart, Paul W Harms, Rajan P Nair, James T Elder, John J Voorhees & Johann E Gudjonsson

  2. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA

    Lam C Tsoi

  3. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA

    Lam C Tsoi

  4. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA

    Celine C Berthier

  5. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Paul W Harms

  6. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA

    James T Elder

  7. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA

    J Michelle Kahlenberg

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Contributions

Y.L., J.E.G., J.T.E., J.M.K. and J.J.V. designed the study and wrote the manuscript; Y.L., X.X., M.A.B., P.W.H., P.E.S., M.K.S., R.P.N. and C.C.B. collected and analyzed data; and L.C.T. and W.R.S. analyzed data. All authors reviewed and commented on the manuscript.

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Correspondence to Johann E Gudjonsson.

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Integrated supplementary information

Supplementary Figure 1 X-inactivation in human skin.

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.

Supplementary Figure 2 Sex differences in expression correlation.

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.

Supplementary Figure 3 Female-biased genes and autoimmune diseases.

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.

Supplementary Figure 4 Knockdown of female-biased transcription factors.

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.

Supplementary Figure 5 eQTL and functional enrichment analyses of VGLL3-regulated genes.

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.

Supplementary Figure 6 VGLL3 targets in autoimmune diseases.

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 information

Supplementary Text and Figures

Supplementary Figures 1–6 (PDF 981 kb)

Supplementary Table 1

Lists of gender biased genes (XLSX 50 kb)

Supplementary Table 2

Details for TF screening for regulation of gender biased genes. (XLSX 35 kb)

Supplementary Table 3

VGLL3-regulated genes in keratinocytes (XLSX 58 kb)

Supplementary Table 4

Overlap between VGLL3-regulated genes and lupus-upregulated genes (XLSX 57 kb)

Supplementary Table 5

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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