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Transcriptomic Characteristics Associated With Aging in the Thyroid Gland.

ABSTRACT: The aging thyroid is associated with a plethora of morphological and functional changes. Limited studies have addressed the gene expression signature in the aging thyroid, except for sporadic reports using data from postmortem samples in the Genotype-Tissue Expression (GTEx) project. In this investigation, we analyzed the RNA sequencing data of 58 samples of normal-appearing counterpart thyroid tissues from The Cancer Genome Atlas. Aging-correlated genes were identified by determining the Spearman rank-order correlation between patient age and gene expression level. Additionally, we performed gene set enrichment analysis and conducted a weighted correlation network analysis. The results were compared with those analyzed using the GTEx data. The over-represented protein class of aging-correlated genes is mainly metabolite interconversion enzymes. Our analyses identified alterations in immune and inflammatory responses, mitochondrial functions, cytoskeletal proteins, as well as amino acid and cytochrome P450 metabolism. There was no significant association between thyroid differentiation and age. Our findings may shed molecular light on thyroid disorders in the geriatric population.

SUBMITTER: Liu CL

PROVIDER: S-EPMC9174607 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Transcriptomic Characteristics Associated With Aging in the Thyroid Gland.

Liu Chien-Liang CL Chien Ming-Nan MN Hsu Yi-Chiung YC Cheng Shih-Ping SP

Frontiers in nutrition 20220525

The aging thyroid is associated with a plethora of morphological and functional changes. Limited studies have addressed the gene expression signature in the aging thyroid, except for sporadic reports using data from postmortem samples in the Genotype-Tissue Expression (GTEx) project. In this investigation, we analyzed the RNA sequencing data of 58 samples of normal-appearing counterpart thyroid tissues from The Cancer Genome Atlas. Aging-correlated genes were identified by determining the Spearm ...[more]

PMID: 35694164

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Project description:Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory-autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves' disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves' disease) and PTC.

Project description:Papillary thyroid carcinoma (PTC) is the fastest-growing disease caused by numerous molecular alterations in addition to previously reported DNA mutations. There is a compelling need to identify novel transcriptomic alterations that are associated with the pathogenesis of PTC with potential diagnostic and prognostic implications. Methods: We gathered and compared 242 expression profiles between paired PTC and adjacent normal tissues and identified and validated the coding and long non-coding RNAs (lncRNAs) associated with the extrathyroidal extension (ETE) of 655 PTC patients in two independent cohorts, followed by predicting their interactions with drugs. Co-expression, RNA interaction, Kaplan-Meier survival and multivariate Cox proportional regression analyses were performed to identify dysregulated lncRNAs and genes that correlated with clinical outcomes of PTC. Alternative splicing (AS), RNA circularization, and editing were also compared between transcriptomes to expand the repertoire of molecular alterations in PTC. Results: Numerous genes related to cellular microenvironment and steroid hormone response were associated with the ETE of PTC. Drug susceptibility predictions of the expression signature revealed two highly ranked compounds, 6-bromoindirubin-3'-oxime and lovastatin. Co-expression and RNA interaction analysis revealed the essential role of lncRNAs in PTC pathogenesis by modulating extracellular matrix and cell adhesion. Eight genes and two novel lncRNAs were identified that correlated with the aggressive nature and disease-free survival of PTC. Furthermore, this study provided the transcriptome-wide landscape of circRNAs in PTC and uncovered dissimilar expression profiles among circRNAs originating from the same host gene, suggesting the functional complexity of circRNAs in PTC carcinogenesis. The newly identified AS events in the SERPINA1 and FN1 genes may improve the sensitivity and specificity of these diagnostic biomarkers. Conclusions: Our study uncovered a comprehensive transcriptomic signature associated with the carcinogenesis and aggressive behavior of PTC, as well as presents a catalog of 10 potential biomarkers, which would facilitate PTC prognosis and development of new therapeutic strategies for this cancer.

Dataset Information

Transcriptomic Characteristics Associated With Aging in the Thyroid Gland.

Publications

Transcriptomic Characteristics Associated With Aging in the Thyroid Gland.

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