TY - JOUR
T1 - The Role of NRG1 in the Predisposition to Papillary Thyroid Carcinoma
AU - He, Huiling
AU - Li, Wei
AU - Liyanarachchi, Sandya
AU - Wang, Yanqiang
AU - Yu, Lianbo
AU - Genutis, Luke K.
AU - Maharry, Sophia
AU - Phay, John E.
AU - Shen, Rulong
AU - Brock, Pamela
AU - De La Chapelle, Albert
N1 - Funding Information:
Financial Support: This work was supported by National Cancer Institute Grants P30CA16058 and P50CA168505.
Publisher Copyright:
© 2018 Endocrine Society.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Context Previous genome-wide association studies have shown that single-nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered. Objective To evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue. Methods Quantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed. Results Three NRG1 isoforms (NM-004495, NM-013958, and NM-001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ∼32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1. Conclusions Our data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC.
AB - Context Previous genome-wide association studies have shown that single-nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered. Objective To evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue. Methods Quantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed. Results Three NRG1 isoforms (NM-004495, NM-013958, and NM-001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ∼32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1. Conclusions Our data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC.
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U2 - 10.1210/jc.2017-01798
DO - 10.1210/jc.2017-01798
M3 - Article
C2 - 29121253
AN - SCOPUS:85045430178
SN - 0021-972X
VL - 103
SP - 1369
EP - 1379
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -