Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Mihaela Stefan, Chengguo Wei, Angela Lombardi, Cheuk Wun Li, Erlinda S. Concepcion, William B. Inabnet, Randall Owen, Weijia Zhang, Yaron Tomer

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic-epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.

Original languageEnglish (US)
Pages (from-to)12562-12567
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number34
DOIs
Publication statusPublished - Aug 26 2014
Externally publishedYes

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Keywords

  • Histone modifications
  • Interferon
  • Thyroiditis

ASJC Scopus subject areas

  • General

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