The human tissue specific proteome
All approximately 20000 human genes are classified according to their expression across a large number of tissues representing all major organs and tissue types in the human body. Almost half of the genes appear as housekeeping genes with detectable levels of transcripts in all analyzed tissues, while approximately 36% show some level of elevated expression in one of the analyzed tissues. The genes with an elevated expression in a particular tissue or organ are of course interesting as starting points to understand the biology and function of this part of the human body, although only a few of these genes show a strict tissue-specific expression in a single tissue or organ. Functional analysis of the tissue elevated proteins is well in line with the function of the respective tissue or organ with the pancreas, salivary gland, liver and bone marrow expressing a large number of secreted proteins, the kidney expressing membrane-bound transport proteins and the brain expressing many proteins involved in nerve cell function.
- 2489 tissue enriched genes
- 1161 group enriched genes
- A total of 7100 genes are elevated in at least one of the analyzed tissues
- Elevated genes encode proteins with functions that correspond well to the overall function of the respective organ
Based on transcriptomics analysis across all major organs and tissue types in the human body, all putative 19692 protein-coding genes are classified according to their pattern of protein expression, including 8588 genes expressed in all tissues (see housekeeping proteome) and those expressed in a differential manner across the human body. Of particular interest are those 7100 proteins showing a significant elevated level of expression in a particular tissue or a group of related tissues. These genes consist of three major subclasses (see Table 1 below); the tissue enriched genes (n=2489), the group enriched genes (n=1161) and the tissue enhanced genes (n=3450).
Figure 1. Pie chart showing the number of genes in the different RNA-based categories of gene expression.
Table 1. The genes with elevated expression
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
The amount of tissue elevated genes is highly variable between the analyzed tissue types (see Table 2 below). The testis shows the largest number of tissue enriched genes (n=1057), followed by the brain (n=381) and the liver (n=170). The large number of genes elevated in testis might in part be due to that the corresponding meiosis specific stage in females have not been analyzed. Some tissues have similar functions and tissue morphology and as expected, tissue elevated genes are predominantly group-enriched genes exemplified by hematopoietic tissues, including spleen and lymph node, and the gastrointestinal tract, including duodenum, small intestine and colon.
Table 2. Tissue elevated genes.
Tissue enriched genes
The comprehensive analysis presented here has identified approximately 3650 human genes that display a tissue or group-enriched expression pattern across the human body. Functional analysis of the corresponding tissue-enriched proteins identified in our analysis is well in line with the overall function of the respective tissue or organ. Thus, the kidney-enriched proteome (n=70) consists of many membrane-bound transport proteins, such as SLC22A8 (organic anion transporter) and AQP2 (collecting duct water channel protein) whereas the most abundant tissue-enriched proteins in liver (n=170) are secreted plasma proteins, such as ALB (albumin) and HP (haptoglobin), and detoxification proteins, such as UGT2B4 (a member of the UDP glucuronosyltransferase family of enzymes) and a large number of proteins belonging to the cytochrome P450 superfamily of enzymes, such as CYP2A13. Highly expressed brain-enriched proteins are glial cell specific proteins such as the astrocyte intermediate filament protein GFAP (glial fibrillary acidic protein) and major constituents of the myelin sheath, including the oligodendrocyte protein MBP (myelin basic protein), as well as transmembrane proteins associated to synaptic vesicles, such as SLC17A7 (a solute carrier family protein). Moreover, the most abundant pancreas-enriched proteins are digestive enzymes, such as CTRB2 (chymotrypsinogen B2) and AMY2A (amylase, alpha 2A), expressed at extraordinary high levels with over 50000 mRNA molecules per cell, whereas the highest abundance of pancreas-enriched proteins derrived from the endocrine cells in islets of Langerhans include INS (insulin) and GCG (glucagon). Other examples of tissue type specific proteins with a direct link to tissue function include the fat-enriched proteins involved in lipid metabolism, such as PLIN1 (Perilipin 1) and FABP4 (fatty acid-binding protein, adipocyte), skin-enriched proteins involved in squamous differentiation and skin barrier function, such as KRT1 (keratins 1) and CASP14 (caspase-14), and testis-enriched proteins involved in meiosis and spermatogenesis, including DMRT1 (Doublesex- and mab-3-related transcription factor 1) and PRM1 (protamin 1).
The antibody-based protein profiling using immunohistochemistry allows for visualization of where in the body proteins that correspond to different tissue elevated genes are expressed and provides a precise map of protein expression in the various compartments and cell types that constitute different tissues and organs.
Below are examples of protein expression patterns of mainly known and well characterized tissue- and group-enriched genes.
- adipose tissue (soft tissue)
- adipose tissue (breast)
Figure 2. Examples of protein expression (brown color) patterns of mainly well-known and characterized tissue- and group-enriched genes.
Table 3. Tissue-specific scores and mRNA levels (measured as FPKM) are given for the above selected examples of tissue type enriched proteins.
||hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
||defensin, alpha 1
||defensin, alpha 5, Paneth cell-specific
||fatty acid binding protein 2, intestinal
||progestagen-associated endometrial protein
||carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4
||troponin I type 3 (cardiac)
||troponin T type 2 (cardiac)
||aquaporin 2 (collecting duct)
||surfactant protein A1
||surfactant protein B
||membrane-spanning 4-domains, subfamily A, member 1
||melanoma associated antigen (mutated) 1-like 1
||amylase, alpha 2A (pancreatic)
||chorionic somatomammotropin hormone 1 (placental lactogen)
||kallikrein-related peptidase 3
||myosin, heavy chain 1, skeletal muscle, adult
||fatty acid binding protein 6, ileal
||pepsinogen 3, group I (pepsinogen A)
||doublesex and mab-3 related transcription factor 1
||thyroid stimulating hormone receptor
* group enriched score for tissue types with similar function and morphology.
In addition to previously known proteins, the analysis also identified a large number of genes with tissue elevated expression patterns that were previously poorly characterized and with no or only scarce evidence of existence on the protein level. The combined RNA- and antibody-based profiling can thus be used to confirm the functional existence of such protein-coding genes lacking previous annotation. These proteins are interesting starting points for further in-depth studies to gain better molecular understanding of the cellular phenotypes that define the function of each respective tissue and organ.
Group enriched proteins
The 1161 genes identified with a group enriched expression pattern reflects genes with shared expression in a limited number of tissues. The function of corresponding proteins may be involved in various traits that can be shared between cell types located in different tissues and organs, such as proteins expressed in inflammatory cells (dominating cell type in lymph node and appendix), proteins involved in squamous differentiation (esophagus and skin), glandular cell function in the gut (duodenum, small intestine and colon) or cilia movement (testis and fallopian tube). The schematic network plot below shows the distribution between tissues of genes with shared expression of group enriched genes.
Figure 3. An interactive network plot of the tissue enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of tissue 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.
Tissue enhanced genes
The category tissue enhanced genes presents specific lists for each included tissue-type and is defined as genes that do not fulfill the criteria of tissue enriched but show a 5-fold higher FPKM level in a specific tissue type compared to the average FPKM value of all 32 analyzed tissue types.
Relevant links and publications
Uhlén et al (2015). Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419
Mardinoglu et al (2014). Defining the Human Adipose Tissue Proteome To Reveal Metabolic Alterations in Obesity. J Proteome Res.
PubMed: 25219818 DOI: 10.1021/pr500586e
Kampf et al (2014). Defining the human gallbladder proteome by transcriptomics and affinity proteomics. Proteomics.
PubMed: 25175928 DOI: 10.1002/pmic.201400201
Lindskog et al (2014). The lung-specific proteome defined by integration of transcriptomics and antibody-based profiling. FASEB J.
PubMed: 25169055 DOI: 10.1096/fj.14-254862
Gremel et al (2014). The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling. J Gastroenterol.
PubMed: 24789573 DOI: 10.1007/s00535-014-0958-7
Kampf et al (2014). The human liver-specific proteome defined by transcriptomics and antibody-based profiling. FASEB J.
PubMed: 24648543 DOI: 10.1096/fj.14-250555
Djureinovic et al (2014). The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol Hum Reprod.
PubMed: 24598113 DOI: 10.1093/molehr/gau018
Fagerberg 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
Microscopical images of normal tissue - Tissue Dictionary (Human Protein Atlas)
Allen Brain Atlas