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

Publication Type:

Journal Article


Nat Immunol, Volume 18, Issue 2, p.152-160 (2017)


Adult, Aged, Aged, 80 and over, asb, 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


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.