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

Mihaela Stefan; Chengguo Wei; Angela LombardiCheuk Wun LiErlinda S. ConcepcionWilliam B. Inabnet IIIRandall OwenWeijia ZhangYaron Tomer

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

【24h】

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

机译：Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相关主题

摘要

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 genomewide 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.

著录项

来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第34期|12562-12567|共6页
作者
Mihaela Stefan; Chengguo Wei; Angela LombardiCheuk Wun LiErlinda S. ConcepcionWilliam B. Inabnet IIIRandall OwenWeijia ZhangYaron Tomer;
展开▼
作者单位

Division of Endocrinology and Departments of Icahn School of Medicine at Mount Sinai, New York, NY 10029;

Medicine Bioinformatics Core and Icahn School of Medicine at Mount Sinai, New York, NY 10029;

James J. Peters Veterans Administration Medical Center, Bronx, NY 10468Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

展开▼
收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
histone modifications; interferon; thyroiditis;

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

摘要

著录项

相关主题

期刊订阅