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% (n=7904) show some level of elevated expression in one of the analyzed tissues. The genes with an elevated expression in a particular tissue are interesting as a starting point 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. Examples include the pancreas, salivary gland, liver, epidymus and bone marrow that express a large number of secreted proteins, the kidney that express membrane-bound transport proteins and the brain that expresses many proteins involved in nerve cell function.

  • 2608 tissue enriched genes
  • 1139 group enriched genes
  • 4157 enhanced genes
  • A total of 7904 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 19613 protein coding genes are classified according to their pattern of protein expression, including 7319 genes expressed in all tissues (see housekeeping proteome) and those expressed in a differential manner across the human body. Of particular interest are those 7904 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=2608), the group enriched genes (n=1139) and the tissue enhanced genes (n=4157).

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 2608 At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
Group enriched 1139 At least five-fold higher mRNA levels in a group of 2-7 tissues
Tissue enhanced 4157 At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
Total 7904 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=1079), followed by the brain (n=419) and the liver (n=157). 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 1079 364 794 2237
Cerebral cortex 419 246 795 1460
Skin 97 133 247 477
Fallopian tube 51 167 209 427
Liver 157 121 148 426
Parathyroid gland 60 63 236 359
Placenta 78 73 205 356
Small intestine 5 168 174 347
Kidney 54 119 161 334
Skeletal muscle 95 122 113 330
Duodenum 5 160 165 330
Spleen 10 50 265 325
Epididymis 93 88 132 313
Bone marrow 73 45 184 302
Lymph node 0 45 234 279
Adrenal gland 33 75 144 252
Esophagus 43 100 108 251
Thyroid gland 21 49 175 245
Heart muscle 28 89 84 201
Appendix 2 47 151 200
Tonsil 6 75 108 189
Lung 18 44 124 186
Prostate 20 51 112 183
Rectum 1 79 92 172
Adipose tissue 20 34 114 168
Colon 2 85 79 166
Stomach 23 46 97 166
Cervix, uterine 5 42 107 154
Gallbladder 3 41 107 151
Seminal vesicle 8 33 96 137
Breast 23 41 66 130
Ovary 6 19 103 128
Endometrium 4 27 87 118
Smooth muscle 0 16 75 91
Salivary gland 30 25 30 85
Pancreas 35 16 21 72
Urinary bladder 1 24 39 64
Total 2608 1139 4157 7904


Tissue enriched genes


The comprehensive analysis presented here has identified approximately 3747 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=54) 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=157) 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 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
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 1012.5
Adrenal gland HSD3B2 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 433 2384.5
Adrenal gland PNMT phenylethanolamine N-methyltransferase 8 226.6
Appendix CD19 CD19 molecule 11* 37.4
Bone marrow DEFA1 defensin alpha 1 269 30312.0
Bone marrow MPO myeloperoxidase 82 2499.6
Duodenum DEFA5 defensin alpha 5 480* 10677.9
Duodenum FABP2 fatty acid binding protein 2 12* 261.4
Endometrium PAEP progestagen associated endometrial protein 7 437.0
Esophagus CRNN cornulin 20 4518.8
Esophagus KRT4 keratin 4 25 14861.9
Gallbladder CHST4 carbohydrate sulfotransferase 4 13 102.5
Heart muscle TNNI3 troponin I3, cardiac type 174 3607.1
Heart muscle TNNT2 troponin T2, cardiac type 203 5120.1
Kidney AQP2 aquaporin 2 132* 435.9
Kidney UMOD uromodulin 726 2392.4
Liver ALB albumin 220 105947.0
Liver HP haptoglobin 182 28407.0
Lung SFTPA1 surfactant protein A1 1180 10513.5
Lung SFTPB surfactant protein B 912 5318.7
Lymph node MS4A1 membrane spanning 4-domains A1 15* 770.3
Ovary MUM1L1 MUM1 like 1 7 226.8
Pancreas AMY2A amylase, alpha 2A (pancreatic) 313 31329.4
Pancreas INS insulin 27 1850.7
Placenta CSH1 chorionic somatomammotropin hormone 1 211 13487.0
Prostate KLK3 kallikrein related peptidase 3 365 12913.0
Salivary gland STATH statherin 1719 44726.6
Skeletal muscle MYH1 myosin heavy chain 1 738 2753.9
Skin KRT1 keratin 1 25 15454.7
Small intestine FABP6 fatty acid binding protein 6 49 4217.5
Spleen CD72 CD72 molecule 8* 64.7
Stomach PGA3 pepsinogen 3, group I (pepsinogen A) 716 6775.4
Testis DMRT1 doublesex and mab-3 related transcription factor 1 107 50.7
Testis PRM2 protamine 2 5145 7760.7
Thyroid gland TG thyroglobulin 1104 15620.0
Thyroid gland TSHR thyroid stimulating hormone receptor 282 445.5
Urinary bladder UPK2 uroplakin 2 44 68.5

* 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 at 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 1139 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 group enriched genes in different tissues.

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 3 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 TPM level in a specific tissue type compared to the average TPM value of all 37 analyzed tissue types.

Relevant links and publications


Uhlén M et al, 2015. Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419

Bergman J et al, 2016. The human adrenal gland proteome defined by transcriptomics and antibody-based profiling. Endocrinology.
PubMed: 27901589 DOI: 10.1210/en.2016-1758

Edqvist PH et al, 2015. Expression of human skin-specific genes defined by transcriptomics and antibody-based profiling. J Histochem Cytochem.
PubMed: 25411189 DOI: 10.1369/0022155414562646

Lindskog C et al, 2015. The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling. BMC Genomics.
PubMed: 26109061 DOI: 10.1186/s12864-015-1686-y

Sjöstedt E et al, 2015. Defining the Human Brain Proteome Using Transcriptomics and Antibody-Based Profiling with a Focus on the Cerebral Cortex. PLoS One.
PubMed: 26076492 DOI: 10.1371/journal.pone.0130028

Zieba A et al, 2015. The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling. OMICS.
PubMed: 26488136 DOI: 10.1089/omi.2015.0115

O'Hurley G et al, 2015. Analysis of the Human Prostate-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling Identifies TMEM79 and ACOXL as Two Putative, Diagnostic Markers in Prostate Cancer. PLoS One.
PubMed: 26237329 DOI: 10.1371/journal.pone.0133449

Andersson S et al, 2014. The transcriptomic and proteomic landscapes of bone marrow and secondary lymphoid tissues. PLoS One.
PubMed: 25541736 DOI: 10.1371/journal.pone.0115911

Habuka M et al, 2014. The kidney transcriptome and proteome defined by transcriptomics and antibody-based profiling. PLoS One.
PubMed: 25551756 DOI: 10.1371/journal.pone.0116125

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

Lindskog C 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 G 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 C 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 D 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 L 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

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

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

RNAseq atlas

Fantom

Uniprot

BioGPS

Allen Brain Atlas