The tissue atlas: the map of the proteins in all human tissues and organs.

Sitting at the lab desk in the late hour of my day, I navigate the web scrolling pages and pages of content to find the information I need to plan my next experiment: which tissue is my protein expressed in? I click dozens and dozens of links that take me from one page to another.

I am confused. I am not a focused cyber-sailor and I usually get lost very easily only to find myself pages away from my true destination. Which tissue is my protein expressed in? I still have no answer.

Frustrated, but happy to read on how to cook the best pizza in the world, I give up. Sounds familiar? Yes, it has probably happened to you as well.
 

Why do you need a map?

In some cases, you know exactly what information you need and where to find it. In others, you will need to make multiple stops on your journey and use multiple resources to reach your destination. The more research you do and the more visual material you have – the better. A good map can guide your way, help you plan your journey, and avoid pitfalls.

 

 

Photo: Cecilia Lindskog, Ph.D., is the Site Director of the Tissue Atlas at the Rudbecklaboratoriet in Uppsala, Sweden.

 

 

Humans have about 25,000 genes. Approximately 20,000 of these genes are protein-coding genes. That means, of course, that humans make at least 20,000 proteins. The human proteome is the entire set of proteins expressed, or that can be expressed, by a genome, cell, tissue, or organism at a certain time. But which tissues are all these proteins located in?

Don’t despair. Luckily for you, scientists have adapted the “mapping approach” to study tissue protein expression at an amazing level.

The Human Protein Atlas (HPA) is a Swedish-based multinational research project supported by the non-profit trust, the Knut and Alice Wallenberg Foundation. The HPA analyzes the human genome on different levels: in organs, tissues, cells, and organelles.

Organs and tissues are stained using immunohistochemistry, providing the basis for the Tissue Atlas and the Pathology Atlas, while cells and organelles are analyzed with immunofluorescence (IF) in the Cell Atlas.

The proteomic analysis is combined with RNA-Seq on the organ, tissue, and cellular level, and all data is freely accessible on the HPA web portal.

 

The Tissue Atlas

The Tissue Atlas was launched in November 2014 as an open-source tissue-based interactive map of the human proteome. It is based on quantitative transcriptomics on a tissue and organ level combined with protein profiling using tissue microarray-based immunohistochemistry to achieve spatial localization of proteins down to the single-cell level.

It offers the possibility to explore the tissue-elevated proteomes in tissues and organs and to analyze tissue profiles for specific protein classes. The HPA compiles comprehensive lists of proteins expressed at elevated levels in the different tissues to provide a spatial context with localization of the proteins in the sub-compartments of each tissue and organ, down to the single-cell level.

 

The Tissue Atlas in numbers

The Tissue Atlas contains a comprehensive summary of both mRNA and protein level expression. The protein expression data, currently covering 15,297 (or about 78%) of the protein-coding genes, is derived from antibody-based protein profiling using IHC on tissue microarrays (TMAs).

To ensure good coverage, the Tissue Atlas uses TMAs to show antibody staining in samples from 144 individuals corresponding to 44 different normal tissue types, and samples from 216 cancer patients corresponding to 20 different types of cancer. 

 

Figure 2. Tissue Microarray or TMA is an ideal method for studying multiple human cancer / normal tissues in a single assay.

Tissue Atlas uses 1 mm tissue cores to represent each sample, which provides 576 images for each antibody. In most cases, samples from three individuals represent normal tissue, and 76 different normal cell types provide information on protein expression in these tissue types. For cancer samples, The Tissue Atlas samples two cores from each individual and annotates protein expression in tumor cells.

Immunohistochemistry staining patterns are manually analyzed by certified pathologists and the data is presented as histology-based annotation of protein expression levels of almost 3 million tissue-based images.  To facilitate integration with other biological resources, all data is available for downloading and cross-referencing.

A tissue map of this size that provides you with microscopic details of tissues and organs of the human body has never been made before. The Tissue Atlas is described in more detail in a paper published in Science (1). Additional information is available on the Human Tissue Proteome pages and in the annotation section.

 

 

Dive and peek deep into the atlas

You could picture the Tissue Atlas database as the proverbial iceberg: what you see floating above the calm cold water is only the tip. About 90% of an iceberg is below the surface of the water. Similarly, the amount of “below-the-surface” data in the Tissue Atlas database is vast and can be difficult to judge just by looking above the surface.

In fact, the deeper you navigate the Tissue Atlas, the more you discover. The Tissue Atlas is so rich and detailed that you might be surprised to find unique information about your protein of interest. 

For example, let’s say you want to know more about the pancreatic lipase protein (PNLIP). You can type in your protein name or click on the pancreas-specific proteome.

You will find a basic description and analyses of expression patterns, gene lists, examples of protein expression on a cellular level, and tons of other useful information such as:

1) protein expression of genes elevated in the pancreas,
2) proteins specifically expressed in islet cells of the pancreas,
3) proteins specifically expressed in exocrine glandular cells of the pancreas,
4) proteins specifically expressed in ductal cells of the pancreas,
5) an interactive network plot of genes shared between the pancreas and other tissues,
6) pancreas function and histology,
7) background with relevant links and publications.

 

 

Still not enough? Explore the database of the image!

Immunohistochemistry has proven its utility to help identify specific cell populations based on a characteristic gene expression signature. It is also useful to precisely define the cell type responsible for the expression of a gene in normal tissues or confirm spatial gene expression differences between species. 

Clicking on the primary data section takes you straight to the stained images from 44 normal human tissues, including 76 distinct cell types. Pathology-based annotation of protein expression has been carried out for all tissues and images. The immunohistochemistry images can be seen in high resolution by clicking on the various tissues.

Figure 3. Example of Mast Cell Expressed Membrane Protein 1 (MCEMP1) staining. MCEMP1, a fairly uncharacterized gene found to encode a single-pass transmembrane protein expressed in human mast cells, displays a group enriched expression in bone marrow, along with lung and appendix. Images from the Human Protein Atlas.

Antibodies have been selected to demonstrate the expression patterns of well-known proteins and to reflect antibodies used in clinical diagnostics to determine the nature of a given cancer. For certain antibodies, the corresponding protein expression pattern is shown in both normal and cancer tissues.  For each exemplified protein there is a short descriptive text including the clinical usefulness of the corresponding antibody.  
 

Understanding disease using the tissue-based atlas

Histology is defined as the study of the microscopical anatomy of cells. Assessment of histology provides important and basic information for our understanding of biology and medicine. Histology is also an integral part of pathology and microscopy-based diagnostics. The Tissue Atlas interactive database is aimed at researchers interested in basic research into human biology as well as those working in translational medicine, enabling them to ask new questions regarding protein expression in different tissues. 

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.  Proteomics studies are, in fact, highly valuable because proteins represent the actual functional molecules in the cell so when mutations occur in the DNA, it is the proteins that are ultimately affected 2. Those genes, and proteins, with an elevated expression in a particular tissue, play important roles in organ physiology and are interesting starting points to understand the biology and function of the human body.

Moreover, a careful examination of relationships between protein expression signatures and clinical pathology parameters can unveil the molecular basis of toxicological effects on pathophysiological pathways at the level of the entire organism. This has important implications for therapeutics, diagnostics, and the identification of new drug targets and biomarkers.

 

Are you ready to dive into it? Type your protein into the Human Protein Atlas and put it into practice!

 

Readings

Uhlen et al, (2015) Tissue-based map of the human proteome. Science, Vol. 347, Issue 6220, 
William C.S.C. (2007) Proteomics Technologies and Challenges. Genomics Proteomics Bioinformatics. 2007; 5(2): 77–85.