Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon α-modulated mechanism

Mihaela Stefan, Eric M. Jacobson, Amanda K. Huber, David A. Greenberg, Cheuk Wun Li, Luce Skrabanek, Erlinda Conception, Mohammed Fadlalla, Kenneth Ho, Yaron Tomer

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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 identifiedTGpromoter 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 5́ 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.

Original languageEnglish (US)
Pages (from-to)31168-31179
Number of pages12
JournalJournal of Biological Chemistry
Issue number36
StatePublished - Sep 9 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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