Tissue-based map of the human proteome

+Author Affiliations

¹Science for Life Laboratory, KTH—Royal Institute of Technology, SE-171 21 Stockholm, Sweden.
²Department of Proteomics, KTH—Royal Institute of Technology, SE-106 91 Stockholm, Sweden.
³Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2970 Hørsholm, Denmark.
⁴Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden·
⁵Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
⁶Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, D-44139 Dortmund, Germany.
⁷Lab Surgpath, Mumbai, India.
⁸Science for Life Laboratory, Department of Neuroscience, Karolinska Institute, SE-171 77 Stockholm, Sweden.
⁹Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.

↵*Corresponding author. E-mail: mathias.uhlen@scilifelab.se

INTRODUCTION

Resolving the molecular details of proteome variation in the different tissues and organs of the human body would greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on quantitative transcriptomics on a tissue and organ level combined with protein profiling using microarray-based immunohistochemistry to achieve spatial localization of proteins down to the single-cell level. We provide a global analysis of the secreted and membrane proteins, as well as an analysis of the expression profiles for all proteins targeted by pharmaceutical drugs and proteins implicated in cancer.

RATIONALE

We have used an integrative omics approach to study the spatial human proteome. Samples representing all major tissues and organs (n = 44) in the human body have been analyzed based on 24,028 antibodies corresponding to 16,975 protein-encoding genes, complemented with RNA-sequencing data for 32 of the tissues. The antibodies have been used to produce more than 13 million tissue-based immunohistochemistry images, each annotated by pathologists for all sampled tissues. To facilitate integration with other biological resources, all data are available for download and cross-referencing.

RESULTS

We report a genome-wide analysis of the tissue specificity of RNA and protein expression covering more than 90% of the putative protein-coding genes, complemented with analyses of various subproteomes, such as predicted secreted proteins (n = 3171) and membrane-bound proteins (n = 5570). The analysis shows that almost half of the genes are expressed in all analyzed tissues, which suggests that the gene products are needed in all cells to maintain “housekeeping” functions such as cell growth, energy generation, and basic metabolism. Furthermore, there is enrichment in metabolism among these genes, as 60% of all metabolic enzymes are expressed in all analyzed tissues. The largest number of tissue-enriched genes is found in the testis, followed by the brain and the liver. Analysis of the 618 proteins targeted by clinically approved drugs unexpectedly showed that 30% are expressed in all analyzed tissues. An analysis of metabolic activity based on genome-scale metabolic models (GEMS) revealed liver as the most metabolically active tissue, followed by adipose tissue and skeletal muscle.

CONCLUSIONS

A freely available interactive resource is presented as part of the Human Protein Atlas portal (www.proteinatlas.org), offering the possibility to explore the tissue-elevated proteomes in tissues and organs and to analyze tissue profiles for specific protein classes. Comprehensive lists of proteins expressed at elevated levels in the different tissues have been compiled to provide a spatial context with localization of the proteins in the subcompartments of each tissue and organ down to the single-cell level.

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The human tissue–enriched proteins.

All tissue-enriched proteins are shown for 13 representative tissues or groups of tissues, stratified according to their predicted subcellular localization. Enriched proteins are mainly intracellular in testis, mainly membrane bound in brain and kidney, and mainly secreted in pancreas and liver.