title: Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon alpha-modulated mechanism.
abstract: Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (-1623A→G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (-1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5' TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon α, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFNα) and genetic (TG) factors to trigger AITD.
authors.affiliation: Division of Endocrinology, Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA. mihaela.stefan@mssm.edu
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stefan
authors.forename: Eric M
authors.initials: EM
authors.lastname: Jacobson
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Huber
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
authors.forename: Cheuk Wun
authors.initials: CW
authors.lastname: Li
authors.forename: Luce
authors.initials: L
authors.lastname: Skrabanek
authors.forename: Erlinda
authors.initials: E
authors.lastname: Conception
authors.forename: Mohammed
authors.initials: M
authors.lastname: Fadlalla
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ho
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D015551:Autoimmunity / Q000235:genetics*; D001665:Binding Sites; D016022:Case-Control Studies; D002460:Cell Line; D044127:Epigenesis, Genetic; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013954:Thyroglobulin / Q000235:genetics*; D013959:Thyroid Diseases / Q000235:genetics* / Q000276:immunology
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D013954:Thyroglobulin