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 journalArticle

42 Citations (Scopus)

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 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
Volume286
Issue number36
DOIs
StatePublished - Sep 9 2011

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Thyroglobulin
Thyroid Diseases
Autoimmunity
Interferon Regulatory Factor-1
Epigenomics
Interferons
Autoimmune Diseases
Thyroid Gland
Single Nucleotide Polymorphism
Nucleotides
Polymorphism
Transcription Factors
Chromatin
Genes
Chromatin Immunoprecipitation
Disease Susceptibility
Association reactions
Histones
Small Interfering RNA
Alleles

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon α-modulated mechanism. / Stefan, Mihaela; Jacobson, Eric M.; Huber, Amanda K.; Greenberg, David A.; Li, Cheuk Wun; Skrabanek, Luce; Conception, Erlinda; Fadlalla, Mohammed; Ho, Kenneth; Tomer, Yaron.

In: Journal of Biological Chemistry, Vol. 286, No. 36, 09.09.2011, p. 31168-31179.

Research output: Contribution to journalArticle

Stefan, Mihaela ; Jacobson, Eric M. ; Huber, Amanda K. ; Greenberg, David A. ; Li, Cheuk Wun ; Skrabanek, Luce ; Conception, Erlinda ; Fadlalla, Mohammed ; Ho, Kenneth ; Tomer, Yaron. / Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon α-modulated mechanism. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 36. pp. 31168-31179.
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