A limited set of transcriptional programs define major histological types and provide the molecular basis for a cellular taxonomy of the human body

Abstract

The ENCODE project has produced a collection of RNA sequencing experiments from many cell lines and bulk tissues that constitutes an extensive catalogue of the expression programs utilized in the human body. However, the relationship between the transcriptomes of tissues and those of the constituent primary cells, and how these impact tissue phenotypes has not been well established. Here we have produced RNA sequencing data for a number of primary cells from ten human body locations. The analysis of this data, together with additional epigenetic data from a total of 146 primary cells, indicates that many cells in the human body belong to five major cell types of similar transcriptional complexity: three, epithelial, endothelial, and mesenchymal, are broadly distributed across the human body acting as components for many tissues and organs, and two, neural and blood cells, are more anatomically localized. Based on gene expression, these redefine the basic histological types by which tissues have been traditionally classified. We have identified genes whose expression is specific to these cell types, and have estimated the relative proportion of the major cell types in human tissues using the transcriptional profiles produced by the GTEx project. The inferred cellular composition is a characteristic signature of tissues and reflects tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex and found that departures from the normal cellular composition correlate with histological phenotypes associated to disease. This transcriptionally based classification of human cells provide a new view of human biology and disease.