Since cytokines are key mediators of tissue inflammation and infiltration, a team of researchers from Mount Sinai School of Medicine in New York City tested the hypothesis that inflammatory cytokines, specifically interferon-alpha, a prime cytokine in the etiology of autoimmune thyroid disease, promote thyroid cell dysfunction through epigenetic modifications of autoimmune thyroid diseases genes. Interferon-alpha (IFNa) has also been shown to precipitate autoimmune thyroid diseases when used as therapeutic agent. The researchers had previously shown that IFNa increases mRNA expression of major AITD susceptibility genes in both cell lines and a mouse model of IFNa thyroid expression.
Researchers mapped modifications of histone patterns [histone H3 mono- and trimethylated at Lys-4 (H3K4me1 and H3K4me3)] induced by IFNa at these loci using ChIP-seq in human thyroid cells. ChIP-seq data were integrated with RNA-seq and bioinformatic analyses. Integration of ChIP-seq and RNA-seq data showed that significantly upregulated pathways included genes characterized by H3K4me3 enrichment in the 5’-regions, demonstrating a correlation between H3K4me3 and pathway activation by IFNa. Most upregulated genes/pathways participate in innate immunity and host defense response. IFNa induced enrichment of H3K4me1 mostly in noncoding gene regions.
Researchers next used the potential of H3K4me1 to mark regulatory regions to identify functional AITD-associated single-nucleotide polymorphisms (SNPs). An AITD-associated SNPs, in thyroglobulin (TG) gene was marked by enrichment of H3K4me1. This same SNP was previously shown by us through bioinformatic analyses followed by ChIP, luciferase reporter, and siRNA assays to bind interferon regulatory factor-1 (IRF1) and to modulate TG promoter activity in an allele-dependent manner.
“It is well-established that autoimmune thyroid diseases result from interactions between genetic and environmental factors. However, until now, the complex interplay between genes and intra- and extra-cellular factors to trigger pathological autoimmune responses has remained undefined,” said Douglas Forrest, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases, and Program Co-Chair of the ATA Annual Meeting.
About the ATA Annual Meeting The 82nd Annual Meeting of the American Thyroid Association is held Sept.19-23, in Québec City, Québec, Canada. This four-day creative and innovative scientific program, chaired by Elizabeth Pearce, MD, Boston Medical Center, and Douglas Forrest, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, carefully balances clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.
About the ATA The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,600 members from 43 countries around the world. Celebrating its 89th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs through www.thyroid.org; and the development of guidelines for clinical management of thyroid disease. Visit www.thyroid.org for more information.
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