The thyroid gland-specific proteome
The main function of the thyroid gland is regulation of metabolic rate. It produces the thyroid hormones T4 and T3, which increase heart rate, respiration and gastrointestinal motility and stimulate carbohydrate and fat metabolism. The thyroid gland also produces calcitonin, a hormone that regulates blood calcium levels. The transcriptome analysis shows that 69% (n=13590) of all human proteins (n=19613) are expressed in the thyroid gland and 245 of these genes show an elevated expression in thyroid gland compared to other tissue types.
An analysis of the genes with elevated expression in the thyroid gland with regards to subcellular localization reveals that the corresponding proteins are predominantly located in the the cytoplasm.
- 21 thyroid gland enriched genes
- Most of the tissue enriched genes encode proteins involved in thyroid hormone synthesis
- 245 genes defined as elevated in the thyroid gland
- Most group enriched genes shared with the testis
Figure 1. The distribution of all genes across the five categories based on transcript abundance in thyroid gland as well as in all other tissues.
245 genes show some level of elevated expression in the thyroid gland compared to other tissues. The three categories of genes with elevated expression in the thyroid gland compared to other organs are shown in Table 1. The list of tissue enriched genes (n=21) are well in-line with the function of the thyroid gland.
In Table 2, the 12 genes with the highest level of expression among 21 enriched genes are defined.
Table 1. Number of genes in the subdivided categories of elevated expression in thyroid gland.
||Number of genes
||At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
||At least five-fold higher mRNA levels in a group of 2-7 tissues
||At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
||Total number of elevated genes in thyroid gland
Table 2. The 12 genes with the highest level of enriched expression in thyroid gland. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. "mRNA (tissue)" shows the transcript level as TPM values, TS-score (Tissue Specificity score) corresponds to the score calculated as the fold change to the second highest tissue.
||thyroid stimulating hormone receptor
||calcitonin related polypeptide beta
||solute carrier family 26 member 4
||recombination activating 2
||solute carrier family 26 member 7
||bone morphogenetic protein 8a
||forkhead box E1
||paired box 8
Some of the proteins predicted to be membrane-spanning are intracellular, e.g. in the Golgi or mitochondrial membranes, and some of the proteins predicted to be secreted can potentially be retained in a compartment belonging to the secretory pathway, such as the ER, or remain attached to the outer surface of the cell membrane by a GPI anchor.
The thyroid gland transcriptome
An analysis of the expression levels of each gene made it possible to calculate the relative mRNA pool for each of the categories. The analysis shows that 85% of the mRNA molecules in the thyroid gland correspond to housekeeping genes and only 6% of the mRNA pool corresponds to genes categorized to be either thyroid gland enriched, group enriched, or enhanced in thyroid. Thus, most of the transcriptional activity in the thyroid gland relates to proteins with presumed housekeeping functions as they are found in all tissues and cells analyzed.
A Gene Ontology analysis shows that a majority of genes and the corresponding proteins are involved in different metabolic processes including thyroid hormone metabolism,
generation and ion transmembrane transport. The most common functions of these proteins are peroxidase and transmembrane transport activity.
Protein expression of genes elevated in thyroid gland
In-depth analysis of the elevated genes in the thyroid gland using antibody-based protein profiling allowed us to understand the distribution of the thyroid specific genes and their expression profiles.
Proteins specifically involved in thyroid hormone synthesis
An essential step of thyroid hormone production is the oxidation of iodide to iodine, which is carried out by the enzyme thyroid peroxidase (TPO). In autoimmune thyroiditis antibodies target this protein leading to underproduction of thyroid hormone. After oxidation iodine is bound to tyrosine amino acids within the thyroid specific protein thyroglobulin and thyroxine is formed. The thyroxine remains bound to the thyroglobulin molecule, and is stored within thyroid follicles. Thyroxine (T4) can be considered a prohormone to the more potent hormone triiodothyronine (T3). T3 is formed from T4 by the action of enzyme deiodinase.
Genes shared between thyroid gland and other tissues
There are 49 group enriched genes expressed in the thyroid gland. Group enriched genes are defined as genes showing a 5-fold higher average level of mRNA expression in a group of 2-7 tissues, including the thyroid gland, compared to all other tissues.
In order to illustrate the relation of the thyroid tissue to other tissue types, a network plot was generated, displaying the number of genes shared between different tissue types.
The thyroid gland did not show a specific pattern of shared group enriched genes with any tissue.
Figure 2. An interactive network plot of the thyroid gland enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of thyroid gland enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 3 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.
Examples of group enriched genes are: NKX2-1, expressed in the thyroid gland and the lung,
is a transcription factor that regulates the expression of thyroid-specific genes but also genes involved in morphogenesis; SLC5A5,
expressed in the thyroid gland, stomach and salivary gland, encodes a member of the sodium glucose co-transporter family and function in iodine uptake;
LRP2, expressed in the thyroid gland, kidney and parathyroid gland, encodes a protein that is critical for the re-uptake of numerous ligands,
including lipoprotein, sterols, vitamin-binding proteins and hormones.
Thyroid gland function
The thyroid gland produces the hormones thyroxine (T4) and triiodothyronine (T3). Follicular cells of the thyroid produce the protein thyroglobulin that is secreted
into the colloid of the thyroid gland. T4 and T3 is formed by iodination of thyroglobulin tyrosine residues. The thyroid gland is stimulated to release T4 and T3
by the pituitary hormone thyroid stimulating hormone (TSH). Increased blood TSH concentration leads to increased release of T4 and T3.
These thyroid hormones control the metabolic rate of the body. An elevated level of these hormones will increase heart rate, respiration, gastrointestinal motility
and stimulate carbohydrate and fat metabolism. A decreased production will have the opposite effect. In the infant and young child normal thyroid function is essential for normal growth and brain development.
The thyroid gland also produces calcitonin, a peptide hormone that decreases plasma concentration of calcium. Calcitonin is secreted from a complete different set of cells
than the T4 and T3 secreting cells, called parafollicular cells, or c-cells.
Thyroid gland anatomy and histology
The thyroid gland is a bi-lobar endocrine gland, located to the lower part of the neck immediately under the thyroid cartilage. The thyroid gland has lobular organization. Thyroglobulin is stored as a homogenous colloid material within densely packed thyroid follicles. The follicles are lined with a single layer of follicular cells. A vascular network surrounds each follicle. Interspersed between the thyroid follicles another group of cells care present, the calcitonin producing parafollicular cells.
The histology of human thyroid gland including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.
Here, the protein-coding genes expressed in the thyroid gland are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize protein expression patterns of proteins that correspond to genes with elevated expression in the thyroid gland.
Transcript profiling and RNA-data analyses based on normal human tissues have been described previously (Fagerberg et al., 2013). Analyses of mRNA expression including over 99% of all human protein-coding genes was performed using deep RNA sequencing of 172 individual samples corresponding to 37 different human normal tissue types. RNA sequencing results of 5 fresh frozen tissues representing normal thyroid gland was compared to 167 other tissue samples corresponding to 36 tissue types, in order to determine genes with elevated expression in thyroid gland. A tissue-specific score, defined as the ratio between mRNA levels in thyroid gland compared to the mRNA levels in all other tissues, was used to divide the genes into different categories of expression.
These categories include: genes with elevated expression in thyroid gland, genes expressed in all tissues, genes with a mixed expression pattern, genes not expressed in thyroid gland, and genes not expressed in any tissue. Genes with elevated expression in thyroid gland were further sub-categorized as i) genes with enriched expression in thyroid gland, ii) genes with group enriched expression including thyroid gland and iii) genes with enhanced expression in thyroid gland.
Human tissue samples used for protein and mRNA expression analyses were collected and handled in accordance with Swedish laws and regulation and obtained from the Department of Pathology, Uppsala University Hospital, Uppsala, Sweden as part of the sample collection governed by the Uppsala Biobank. All human tissue samples used in the present study were anonymized in accordance with approval and advisory report from the Uppsala Ethical Review Board.
Relevant links and publications
Uhlén M et al, 2015. Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419
Yu NY et al, 2015. Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res.
PubMed: 26117540 DOI: 10.1093/nar/gkv608
Fagerberg L et al, 2014. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics.
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600
Histology dictionary - the thyroid gland
EndocrineWeb - Symptoms and causes of endocrine disorders and how they can be treated.