title: A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.
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.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Beamer
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Sarkar
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Paul W
authors.identifier: 0000-0002-0802-2883
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.|Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: J Michelle
authors.identifier: 0000-0002-4006-8945
authors.initials: JM
authors.lastname: Kahlenberg
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci; D012595:Scleroderma, Systemic / Q000235:genetics*; D012737:Sex Factors; D012859:Sjogren's Syndrome / Q000235:genetics*; D012867:Skin / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D014157:Transcription Factors; C555441:VGLL3 protein, human