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

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.

• Authors: Mihaela Stefan, Chengguo Wei, Angela Lombardi, Cheuk Wun Li, Erlinda S Concepcion, William B Inabnet 3rd, Randall Owen, Weijia Zhang, Yaron Tomer
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 34 Pg. 12562-7 (Aug 26 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25122677 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histones
• Interferon-alpha
• Kruppel-Like Transcription Factors
• Promyelocytic Leukemia Zinc Finger Protein
• RNA, Messenger
• Receptors, Thyrotropin
• ZBTB16 protein, human

Topics

• Autoimmunity (genetics)
• Binding Sites (genetics)
• Cell Line
• Epigenesis, Genetic
• Gene Expression Regulation
• Gene-Environment Interaction
• Graves Disease (etiology, genetics, immunology)
• Histones (chemistry, metabolism)
• Humans
• Interferon-alpha (immunology, pharmacology)
• Introns
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Methylation
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Promyelocytic Leukemia Zinc Finger Protein
• RNA, Messenger (genetics, metabolism)
• Receptors, Thyrotropin (genetics, immunology)
• Thymus Gland (immunology, metabolism)
• Thyroid Gland (immunology, metabolism)