The pancreas-specific proteome

The pancreas transcriptome

Transcriptome analysis of the pancreas 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 pancreas compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in pancreas 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 pancreas 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 pancreas compared to other tissues. As evident in Table 1, all genes elevated in pancreas 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

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

As shown in Figure 1, 422 genes show some level of elevated expression in the pancreas compared to other tissues. The three categories of genes with elevated expression in pancreas compared to other organs are shown in Table 1. In Table 2, the 12 genes with the highest enrichment in pancreas are defined.

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

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

Protein expression of genes elevated in the pancreas

In-depth analysis of the elevated genes in pancreas using antibody-based protein profiling allowed us to visualize the expression patterns of these proteins in different compartments including islets of Langerhans, exocrine glands and ducts.

Proteins specifically expressed in islet cells of pancreas

The islet cells constitute 2% of the pancreas and are responsible for maintaining a steady blood glucose level by secreting hormones regulating uptake and release of glucose. Examples of proteins expressed in islet cells include INS, which is secreted following elevated blood glucose levels and stimulates glucose uptake upon binding insulin receptor, and, GCG, which elicits an opposite effect by raising blood glucose levels. Another important protein is IAPP, a hormone that regulates glucose metabolism and acts as a satiation signal.

INS
GCG
IAPP

Proteins specifically expressed in exocrine glandular cells of pancreas

The exocrine part of the pancreas is mainly composed of exocrine glandular cells and ductal cells. The main function of the exocrine glandular cells is to produce digestive enzymes and chloride-rich fluid for the transportation of enzymes. Examples of proteins expressed in exocrine glandular cells include AMY2A and CELA3A both involved in enzymatic digestion of proteins and lipids. Another example is CPA1 involved in inhibiting early activation of the proenzymes to be secreted.

AMY2A
CELA3A
CPA1

Proteins specifically expressed in ductal cells of pancreas

The enzymes secreted by exocrine glandular cells are transported through the pancreatic ductal system which leads to the duodenum. The ductal epithelium secretes bicarbonate-rich fluid for the regulation of pH. One example of a protein expressed in ductal cells is the SCTR, which is involved in regulating bicarbonate and electrolyte secretion by the pancreas. Other genes found in pancreatic ducts are CFTR, an ion transporter, and DCDC2, a protein shown to bind tubulin and stimulate its polymerization.

SCTR
CFTR
DCDC2

Gene expression shared between pancreas and other tissues

There are 93 group enriched genes expressed in pancreas. 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 pancreas, compared to all other tissues.

In order to illustrate the relation of pancreas 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 pancreas enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of pancreas 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 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

The liver shares group enriched gene expression with many other tissues. One example is GATM, a mitochondrial enzyme that takes part in the biosynthesis of creatine and is expressed mainly in the pancreas, liver and kidney.

GATM - pancreas
GATM - liver
GATM - kidney

The pancreas shares group enriched gene expression of four genes with the salivary gland, an organ with an exocrine function highly correlated with the exocrine pancreas. One of these is BHLHA15, a transcription factor regulating acinar cell function and stability.

BHLHA15 - pancreas
BHLHA15 - salivary gland

The Lithostathine-1-alpha (REG1A), also known as Regenerating islet-derived protein 1-alpha, is expressed throughout the exocrine pancreas and is believed to be important for islet cell regeneration. REG1A is tissue enriched in the pancreas but also expressed in the small intestine and duodenum.

REG1A - pancreas
REG1A - small intestine
REG1A - duodenum

Pancreas function

The pancreas is a mixed exocrine/endocrine gland with dual functions essential for maintaining physiological levels of blood glucose and for digestion of food intake. The underlying cell types that execute these diverse functions are exocrine cells, responsible for storing enzymes, and cells in islets of Langerhans, synthesizing different hormones.

Pancreas histology

The exocrine component is composed of lobular units of acini, which discharge their secretions into progressively larger ducts that finally merge into the main pancreatic duct, which ends in the duodenum. The pyramidal-shaped acinar cells are filled with eosinophilic zymogen granules.

The islets of Langerhans, which constitute 1-2% of the cell mass in the adult pancreas, represent the endocrine component of the pancreas. The islets are round, compact structures that are highly vascularized with sparse connective tissue. The main cell types in the islets are beta cells - responsible for insulin production, alpha cells - responsible for glucagon secretion, delta cells - responsible for somatostatin secretion and PP cells - the pancreatic polypeptide secreting cells.

Using light sheet microscopy and immunostaining we are able to study and visualize the complexity of the pancreas in detail. The video below visualizes the location of insulin localized to the beta cells in islets of Langerhans, in green, and the nerves surrounding the blood vessels which are seen in red. Full length version of the video is found here.

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

Background

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

Transcript profiling was based on a combination of three transcriptomics datasets (HPA, GTEx and FANTOM5), corresponding to a total of 9332 samples from 113 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

Danielsson A et al., The human pancreas proteome defined by transcriptomics and antibody-based profiling. PLoS One. (2014)
PubMed: 25546435 DOI: 10.1371/journal.pone.0115421

Histology dictionary - pancreas