THE HUMAN PROTEOME

? »

The Human Proteome > Tissue specific

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 34% 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.

  • 2355 tissue enriched genes
  • 1109 group enriched genes
  • A total of 6942 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 20344 protein-coding genes are classified according to their pattern of protein expression, including 8874 genes expressed in all tissues (see housekeeping proteome) and those expressed in a differential manner across the human body. Of particular interest are those 6942 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=2355), the group enriched genes (n=1109) and the tissue enhanced genes (n=3478).

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

Category

Number of genes

Description

Tissue enriched 2355 At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
Group enriched 1109 At least five-fold higher mRNA levels in a group of 2-7 tissues
Tissue enhanced 3478 At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
Total 6942 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=999), followed by the brain (n=318) and the liver (n=172). 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 999 317 609 1925
Cerebral cortex 318 226 590 1134
Liver 172 147 156 475
Fallopian tube 60 167 212 439
Skin 97 116 204 417
Kidney 68 149 189 406
Skeletal muscle 111 141 135 387
Bone marrow 85 40 210 335
Small intestine 4 185 139 328
Duodenum 8 184 133 325
Placenta 86 62 146 294
Heart muscle 33 132 117 282
Esophagus 43 111 127 281
Tonsil 6 95 156 257
Adrenal gland 38 88 128 254
Lymph node 0 40 185 225
Spleen 8 47 145 200
Salivary gland 45 54 96 195
Thyroid gland 23 40 130 193
Stomach 28 59 100 187
Rectum 1 108 78 187
Colon 0 110 76 186
Lung 17 48 101 166
Prostate 21 50 88 159
Pancreas 44 44 60 148
Adipose tissue 21 34 90 145
Ovary 6 26 106 138
Gallbladder 6 49 83 138
Appendix 2 47 77 126
Endometrium 4 32 65 101
Urinary bladder 1 23 66 90
Smooth muscle 0 18 57 75
Total 2355 1109 3478 6942


Tissue enriched genes


The comprehensive analysis presented here has identified approximately 3464 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=68) 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=172) 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.

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
FLG2 - skin


KRT1 - skin
FABP6 - small intestine
CD72 - spleen


PGA3 - stomach
DMRT1 - testis
PRM2 - testis


TG - thyroid gland
TSHR - 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 FPKM) are given for the above selected examples of tissue type enriched proteins.

Tissue

Gene

Description

Tissue specific
score

mRNA level
(FPKM)

Adipose tissue PLIN1 perilipin 1 29 580.4
Adrenal gland HSD3B2 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 417 1466.8
Adrenal gland PNMT phenylethanolamine N-methyltransferase 17 121.0
Appendix CD19 CD19 molecule 9* 39.8
Bone marrow DEFA1 defensin, alpha 1 533 23277.3
Bone marrow MPO myeloperoxidase 136 1627.8
Colon KRT20 keratin 20 6* 538.5
Duodenum DEFA5 defensin, alpha 5, Paneth cell-specific 213* 5093.0
Duodenum FABP2 fatty acid binding protein 2, intestinal 10* 192.5
Endometrium PAEP progestagen-associated endometrial protein 13* 143.2
Esophagus CRNN cornulin 12 2295.7
Esophagus KRT4 keratin 4 8 6514.6
Gallbladder CHST4 carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4 12 68.2
Heart muscle TNNI3 troponin I type 3 (cardiac) 325 2157.7
Heart muscle TNNT2 troponin T type 2 (cardiac) 100 2694.0
Kidney AQP2 aquaporin 2 (collecting duct) 169 297.9
Kidney UMOD uromodulin 779 1425.8
Liver ALB albumin 25 16904.3
Liver HP haptoglobin 112 18705.3
Lung SFTPA1 surfactant protein A1 1308 5366.0
Lung SFTPB surfactant protein B 656 2617.1
Lymph node MS4A1 membrane-spanning 4-domains, subfamily A, member 1 11* 583.2
Ovary MUM1L1 melanoma associated antigen (mutated) 1-like 1 8 168.0
Pancreas AMY2A amylase, alpha 2A (pancreatic) 114 31836.8
Pancreas INS insulin 88 2140.4
Placenta CSH1 chorionic somatomammotropin hormone 1 (placental lactogen) 260 8705.6
Prostate KLK3 kallikrein-related peptidase 3 943 5562.0
Salivary gland STATH statherin 588 30871.9
Skeletal muscle MYH1 myosin, heavy chain 1, skeletal muscle, adult 508 1834.3
Skin FLG2 filaggrin family member 2 330 353.2
Skin KRT1 keratin 1 157 5350.5
Small intestine FABP6 fatty acid binding protein 6, ileal 27 1394.9
Spleen CD72 CD72 molecule 7* 80.7
Stomach PGA3 pepsinogen 3, group I (pepsinogen A) 1669 18178.2
Testis DMRT1 doublesex and mab-3 related transcription factor 1 79 35.6
Testis PRM2 protamine 2 2579 2441.8
Thyroid gland TG thyroglobulin 737 4999.8
Thyroid gland TSHR thyroid stimulating hormone receptor 162 332.8
Urinary bladder UPK2 uroplakin 2 39 53.9

* 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 1109 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 toá4átissues, 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.


Uhlen et al (2015). Tissue-based map of the human proteome. Science.
DOI: 10.1126/science.1260419

Mardinoglu A, Kampf C, Asplund A, Fagerberg L, Hallstr÷m BM, Edlund K, BlŘher M, PontÚn F, UhlÚn M, Nielsen J. (2014). Defining the Human Adipose Tissue Proteome To Reveal Metabolic Alterations in Obesity. J Proteome Res.
PubMed: 25219818

Kampf C, Mardinoglu A, Fagerberg L, Hallstr÷m BM, Danielsson A, Nielsen J, PontÚn F, UhlÚn M. (2014). Defining the human gallbladder proteome by transcriptomics and affinity proteomics. Proteomics.
DOI:10.1002/pmic.201400201. PubMed: 25175928

Lindskog C, Fagerberg L, Hallstr÷m B, Edlund K, Hellwig B, RahnenfŘhrer J, Kampf C, UhlÚn M, PontÚn F, Micke P. (2014). The lung-specific proteome defined by integration of transcriptomics and antibody-based profiling. FASEB J.
PubMed: 25169055

Gremel G, Wanders A, Cedernaes J, Fagerberg L, Hallstr÷m B, Edlund K, Sj÷stedt E, UhlÚn M, PontÚn F. (2014). The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling. J Gastroenterol.
PubMed: 24789573

Kampf C, Mardinoglu A, Fagerberg L, Hallstr÷m BM, Edlund K, Lundberg E, PontÚn F, Nielsen J, UhlÚn M. (2014). The human liver-specific proteome defined by transcriptomics and antibody-based profiling. FASEB J.
DOI:10.1096/fj.14-250555. PubMed: 24648543

Djureinovic D, Fagerberg L, Hallstr÷m B, Danielsson A, Lindskog C, UhlÚn M, PontÚn F. (2014). The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol Hum Reprod.
DOI:10.1093/molehr/gau018. PubMed: 24598113

Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics

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

RNA-seq atlas

Fantom

Uniprot

BioGPS

Allen Brain Atlas

The human tissue specific proteome
Tissue enriched genes
Group enriched proteins
Tissue enhanced genes
Relevant links and publications