THE HUMAN TISSUE PROTEOMES

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 40% 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 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.

  • 2547 tissue enriched genes
  • 1126 group enriched genes
  • 4162 enhanced genes
  • A total of 7835 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 19628 protein coding genes are classified according to their pattern of protein expression, including 7367 genes expressed in all tissues (see housekeeping proteome) and those expressed in a differential manner across the human body. Of particular interest are those 7835 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=2547), the group enriched genes (n=1126) and the tissue enhanced genes (n=4162).

Figure 1. Pie chart showing the number of genes in the different RNAbased categories of gene expression.


Table 1. The genes with elevated expression

Category

Number of genes

Description

Tissue enriched 2547 At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
Group enriched 1126 At least five-fold higher mRNA levels in a group of 2-7 tissues
Tissue enhanced 4162 At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
Total 7835 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=1035), followed by the brain (n=415) and the liver (n=156). 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

Tissue
enriched

Group
enriched

Tissue
enhanced

Total
elevated

Testis 1035 363 802 2200
Cerebral cortex 415 239 783 1437
Skin 92 126 241 459
Fallopian tube 51 170 204 425
Liver 156 121 145 422
Placenta 78 75 201 354
Parathyroid gland 56 64 231 351
Small intestine 6 164 173 343
Spleen 10 54 271 335
Duodenum 5 156 170 331
Epididymis 96 85 147 328
Kidney 53 116 156 325
Skeletal muscle 93 118 109 320
Bone marrow 70 46 184 300
Lymph node 0 47 227 274
Esophagus 43 102 109 254
Adrenal gland 33 76 138 247
Thyroid gland 21 50 174 245
Appendix 2 51 152 205
Heart muscle 28 92 81 201
Tonsil 6 77 112 195
Lung 19 44 120 183
Rectum 1 78 94 173
Prostate 20 48 100 168
Adipose tissue 17 34 115 166
Colon 1 84 80 165
Stomach 23 47 91 161
Cervix, uterine 5 39 108 152
Gallbladder 4 40 107 151
Breast 24 42 68 134
Seminal vesicle 8 29 95 132
Ovary 6 18 101 125
Endometrium 4 26 86 116
Smooth muscle 0 15 75 90
Salivary gland 30 24 32 86
Pancreas 35 21 15 71
Urinary bladder 1 24 43 68
Total 2547 1126 4162 7835


Tissue enriched genes


The comprehensive analysis presented here has identified approximately 3673 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=53) 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=156) 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 derived 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 skin and group enriched genes.

FABP4 - adipose tissue (soft tissue)
PLIN1 - adipose tissue (breast)
HSD3B2 - adrenal gland


PNMT - adrenal gland
CD19 - appendix
MPO - bone marrow


DEFA1 - bone marrow
GFAP - cerebral cortex
MBP - hippocampus


KRT20 - colon
DEFA5 - duodenum
FABP2 - duodenum


CRNN - esophagus
KRT4 - esophagus
CHST4 - gallbladder


TNNI3 - heart muscle
TNNT2 - heart muscle
AQP2 - kidney


UMOD - kidney
ALB - liver
HP - liver


SFTPA1 - lung
SFTPB - lung
CD22 - lymph node


MS4A1 - lymph node
MUM1L1 - ovary
AMY2A - pancreas


INS - pancreas
CSH1 - placenta
KLK3 - prostate


STATH - salivary gland
MYH1 - skeletal muscle
KRT1 - skin


FABP6 - small intestine
CD72 - spleen
PGA3 - stomach


DMRT1 - testis
PRM2 - testis
TG - thyroid gland


TPO - thyroid gland
UPK2 - urinary bladder
PAEP - endometrium

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 TPM) are given for the above selected examples of tissue type enriched proteins.

Tissue

Gene

Description

Tissue specific
score

mRNA level
(TPM)

Adipose tissue PLIN1 perilipin 1 10 1011.2
Adrenal gland HSD3B2 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 436 2394.6
Adrenal gland PNMT phenylethanolamine N-methyltransferase 8 227.7
Appendix CD19 CD19 molecule 11* 38.8
Bone marrow DEFA1 defensin, alpha 1 284 15680.7
Bone marrow MPO myeloperoxidase 81 2504.1
Duodenum DEFA5 defensin, alpha 5, Paneth cell-specific 462* 10985.4
Duodenum FABP2 fatty acid binding protein 2, intestinal 12* 268.5
Endometrium PAEP progestagen-associated endometrial protein 7 437.4
Esophagus CRNN cornulin 19 4534.5
Esophagus KRT4 keratin 4, type II 24 14911.0
Gallbladder CHST4 carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4 13 102.9
Heart muscle TNNI3 troponin I type 3 (cardiac) 158 3237.3
Heart muscle TNNT2 troponin T type 2 (cardiac) 199 5036.0
Kidney AQP2 aquaporin 2 (collecting duct) 93* 432.9
Kidney UMOD uromodulin 718 2377.1
Liver ALB albumin 221 105632.0
Liver HP haptoglobin 181 28321.0
Lung SFTPA1 surfactant protein A1 1177 10520.7
Lung SFTPB surfactant protein B 911 5334.1
Lymph node MS4A1 membrane-spanning 4-domains, subfamily A, member 1 15* 780.6
Ovary MUM1L1 melanoma associated antigen (mutated) 1-like 1 7 225.9
Pancreas AMY2A amylase, alpha 2A (pancreatic) 313 31311.3
Pancreas INS insulin 27 1850.8
Placenta CSH1 chorionic somatomammotropin hormone 1 (placental lactogen) 214 13476.0
Prostate KLK3 kallikrein-related peptidase 3 369 12913.7
Salivary gland STATH statherin 1726 45012.6
Skeletal muscle MYH1 myosin, heavy chain 1, skeletal muscle, adult 735 2754.7
Skin KRT1 keratin 1, type II 25 15496.7
Small intestine FABP6 fatty acid binding protein 6, ileal 50 4287.7
Spleen CD72 CD72 molecule 8* 65.9
Stomach PGA3 pepsinogen 3, group I (pepsinogen A) 480 35557.1
Testis DMRT1 doublesex and mab-3 related transcription factor 1 107 50.7
Testis PRM2 protamine 2 5039 7760.1
Thyroid gland TG thyroglobulin 1097 15544.0
Thyroid gland TSHR thyroid stimulating hormone receptor 277 443.8
Urinary bladder UPK2 uroplakin 2 46 71.3

* 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 1126 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 theátissueáenriched and group enriched genes connected to their respective enriched tissues (grey circles).áRedánodes represent the number ofátissue enriched genes andáorangeánodes 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 toá3átissues, 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 skintype and is defined as genes that do not fulfill the criteria of tissue enriched but show a 5-fold higher TPM level in a specific tissue type compared to the average TPM value of all 37 analyzed tissue types.


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Microscopical images of normal tissue - Tissue Dictionary (Human Protein Atlas)

RNAseq atlas

Fantom

Uniprot

BioGPS

Allen Brain Atlas