The gallbladder-specific proteome

The gallbladder is an organ just under the liver connected to the duodenum, and the purpose of the gallbladder is to store bile, a yellow-brown liquid produced by the hepatocytes in the liver, which enables the digestion of fats. During the storage, water and electrolytes are removed from the bile through an active sodium ion transport across the simple columnar epithelium of the gallbladder, which produces concentrated bile. Transcriptome analysis shows that 75% (n=14840) of all human proteins (n=19670) are expressed in the gallbladder and 161 of these genes show an elevated expression in the gallbladder compared to other tissue types.

  • 161 elevated genes
  • 3 enriched genes
  • 41 group enriched genes
  • Gallbladder has most group enriched gene expression in common with tissues in the digestive system and liver


The gallbladder transcriptome

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

  • Tissue enriched: At least four-fold higher mRNA level in gallbladder 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 gallbladder 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 gallbladder compared to other tissues. As evident in Table 1, all genes elevated in gallbladder 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 gallbladder as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (NX?1) in gallbladder as well as in all other tissues.


As shown in Figure 1, 161 genes show some level of elevated expression in the gallbladder compared to other tissues. The three categories of genes with elevated expression in gallbladder compared to other organs are shown in Table 1. In Table 2, the 3 enriched genes are defined.

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

Distribution in the 37 tissues
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Tissue enriched 0210 3
Group enriched 027131 41
Tissue enhanced 124893 117
Total 1531034 161

Table 2. The 3 genes with enriched expression in gallbladder. "Tissue distribution" describes the transcript detection (NX≥1) in gallbladder as well as in all other tissues. "mRNA (tissue)" shows the transcript level in gallbladder as NX values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in gallbladder and the tissue with second highest expression level.

Gene Description Tissue distribution mRNA (tissue) Tissue specificity score
FGF19 fibroblast growth factor 19 Detected in some 62.4 13
CHST4 carbohydrate sulfotransferase 4 Detected in some 46.9 5
MOGAT1 monoacylglycerol O-acyltransferase 1 Detected in many 40.9 5


Protein expression of genes elevated in gallbladder

In-depth analysis of the elevated genes in the gallbladder using antibody-based protein profiling allowed us to visualize the expression patterns of these proteins within the gallbladder. The gallbladder is part of the biliary system which refers to the liver, gallbladder and bile ducts. Examples of proteins with elevated expression in the gallbladder include CHST4, MUC5B and TFF1.


CHST4 - gallbladder

CHST4 - pancreas


MUC5B - gallbladder

MUC5B - salivary gland


TFF1 - stomach

TFF1 - gallbladder


Gene expression shared between gallbladder and other tissues

There are 41 group enriched genes expressed in gallbladder. 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 gallbladder, compared to all other tissues.

In order to illustrate the relation of gallbladder 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 gallbladder enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of gallbladder 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 proteins with shared expression in the gallbladder and other tissues include FXYD2 and TM4SF4.


FXYD2 - gallbladder

FXYD2 - kidney

FXYD2 - salivary gland


TM4SF4 - gallbladder

TM4SF4 - liver

TM4SF4 - small intestine


Gallbladder function

The main function of the gallbladder is to concentrate, store and release bile into the small intestine. Bile is a yellow-brown liquid produced by the hepatocytes in the liver. The release of bile is stimulated by the presence of dietary fats in the small intestine where it acts as a surfactant to emulsify and digest lipids from the food.


Gallbladder histology

The gallbladder sac is attached to the posterior surface of the right lobe of the liver. It is divided into the fundus, body and neck.

The wall of the gallbladder is composed of three layers: mucosa, muscularis, and serosa. There are no muscularis mucosae or submucosa. The mucosa is made up of branching folds lined by a single layer of columnar cells having a pale cytoplasm. The lamina propria encompasses loose connective tissue, blood vessels, nerves, and sparse plasma cells. The muscularis is made up of randomly distributed smooth muscle fibers.

The histology of human gallbladder including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.


Background

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


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

Kampf C et al., Defining the human gallbladder proteome by transcriptomics and affinity proteomics. Proteomics. (2014)
PubMed: 25175928 DOI: 10.1002/pmic.201400201

Histology dictionary - the gallbladder