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 Sj��gren'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.
