The thyroid gland-specific proteome

The main function of the thyroid gland is the regulation of metabolic rate. It produces the thyroid hormones thyroxine (T4) and triiodothyronine (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. Transcriptome analysis shows that 74% (n=14463) of all human proteins (n=19670) are expressed in the thyroid gland and 199 of these genes show an elevated expression in the thyroid gland compared to other tissue types.

  • 199 elevated genes
  • 13 enriched genes
  • 32 group enriched genes
  • Thyroid gland has most group enriched gene expression in common with brain


The thyroid gland transcriptome

Transcriptome analysis of the thyroid gland can be visualized with regard to specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the thyroid gland compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

  • Tissue enriched: At least four-fold higher mRNA level in thyroid gland compared to any other tissues.
  • Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
  • Tissue enhanced: At least four-fold higher mRNA level in thyroid gland compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes that have, or do not have, detectable levels (NX≥1) of transcribed mRNA molecules in the thyroid gland compared to other tissues. As evident in Table 1, all genes elevated in thyroid gland are categorized as:

  • Detected in single: Detected in a single tissue
  • Detected in some: Detected in more than one but less than one third of tissues
  • Detected in many: Detected in at least a third but not all tissues
  • Detected in all: Detected in all tissues

A. Specificity

B. Distribution

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in thyroid gland as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (NX?1) in thyroid gland as well as in all other tissues.

As shown in Figure 1, 199 genes show some level of elevated expression in the thyroid gland compared to other tissues. The three categories of genes with elevated expression in thyroid gland compared to other organs are shown in Table 1. In Table 2, the 12 genes with the highest enrichment in thyroid gland are defined.

Table 1. Number of genes in the subdivided categories of elevated expression in thyroid gland.

Distribution in the 37 tissues
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Tissue enriched 0841 13
Group enriched 015161 32
Tissue enhanced 4358926 154
Total 45810928 199

Table 2. The 12 genes with the highest level of enriched expression in thyroid gland. "Tissue distribution" describes the transcript detection (NX?1) in thyroid gland as well as in all other tissues. "mRNA (tissue)" shows the transcript level in thyroid gland as NX values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in thyroid gland and the tissue with second highest expression level.

Gene Description Tissue distribution mRNA (tissue) Tissue specificity score
TG thyroglobulin Detected in some 994.3 247
TPO thyroid peroxidase Detected in some 411.3 58
SLC26A4 solute carrier family 26 member 4 Detected in some 79.2 24
IYD iodotyrosine deiodinase Detected in some 212.3 16
SLC26A7 solute carrier family 26 member 7 Detected in some 194.5 15
ZNF804B zinc finger protein 804B Detected in some 31.4 9
TSHR thyroid stimulating hormone receptor Detected in some 158.0 6
FOXE1 forkhead box E1 Detected in some 115.1 6
ID4 inhibitor of DNA binding 4, HLH protein Detected in all 154.6 5
BMP8A bone morphogenetic protein 8a Detected in many 45.6 5
GOLGA8Q golgin A8 family member Q Detected in many 18.7 5
PKHD1L1 PKHD1 like 1 Detected in many 91.7 4


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 visualize the expression of the corresponding genes.

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 enzyme leading to underproduction of thyroid hormone. After oxidation of iodide to iodine, iodine is bound to tyrosine amino acids within the thyroid-specific protein thyroglobulin (TG) and thyroxine (T4) 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 iodotyrosine deiodinase (IYD).


TPO

TG

IYD


Gene expression shared between thyroid gland and other tissues

There are 32 group enriched genes expressed in thyroid gland. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including thyroid gland, compared to all other tissues.

In order to illustrate the relation of thyroid gland tissue to other tissue types, a network plot was generated, displaying the number of genes with shared expression between different tissue types.

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 gene expression include NKX2-1, a transcription factor, expressed in the thyroid gland and lung. NKX2-1 regulates the expression of thyroid-specific genes but also genes involved in morphogenesis. Another example is PAX8, expressed in the thyroid gland and the kidney, and that encodes a transcription factor crucial for the development of these organs. Dysregulation of PAX8 has been observed in thyroid cancers.


NKX2-1 - thyroid gland

NKX2-1 - lung


PAX8 - thyroid gland

PAX8 - kidney


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 are formed by iodination of thyroglobulin tyrosine residues. The thyroid gland is stimulated to release T4 and T3 by thyroid stimulating hormone (TSH), produced in the pituitary. 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. And a decreased production will in turn have the opposite effect. For infants and younger children, normal thyroid function is essential for normal growth and brain development.

The thyroid gland also produces calcitonin, a peptide hormone that decreases the plasma concentration of calcium. Calcitonin is secreted from a completely different set of cells than the T4 and T3 secreting cells, called parafollicular cells, or c-cells.


Thyroid gland 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 a lobular organization. Thyroglobulin is stored as a homogeneous 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 are present, the calcitonin producing parafollicular cells.

The histology of human thyroid gland including detailed images and information can be viewed in the Protein Atlas Histology Dictionary.


Background

Here, the protein-coding genes expressed in thyroid gland are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in thyroid gland.


Transcript profiling was based on a combination of three transcriptomics datasets (HPA, GTEx and FANTOM5, corresponding to a total of 483 samples from 37 different human normal tissue types. The final consensus normalized expression (NX) value for each tissue type was used for classification of all genes according to the tissue specific expression into two different categories, based on specificity or distribution.


Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY et al., Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. (2015)
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Histology dictionary - the thyroid gland