A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.
Yun Liang, Lam C Tsoi, Xianying Xing, Maria A Beamer, William R Swindell, Mrinal K Sarkar, Celine C Berthier, Philip E Stuart, Paul W Harms, Rajan P Nair, James T Elder, John J Voorhees, J Michelle Kahlenberg, Johann E Gudjonsson
Author Information
- Yun Liang: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Lam C Tsoi: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Xianying Xing: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Maria A Beamer: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- William R Swindell: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Mrinal K Sarkar: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Celine C Berthier: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
- Philip E Stuart: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- Paul W Harms: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. ORCID
- Rajan P Nair: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- James T Elder: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- John J Voorhees: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
- J Michelle Kahlenberg: Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA. ORCID
- Johann E Gudjonsson: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
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.
Adult
Aged
Aged, 80 and over
Cells, Cultured
Female
Gene Expression Profiling
Gene Regulatory Networks
Genetic Association Studies
Genome-Wide Association Study
Humans
Keratinocytes
Lupus Erythematosus, Cutaneous
Male
Middle Aged
Quantitative Trait Loci
Scleroderma, Systemic
Sex Factors
Sjogren's Syndrome
Skin
Transcription Factors
Transcriptome
Young Adult
Transcription Factors
VGLL3 protein, human
