Cellular Deconstruction: Finding Meaning in Individual Cell Variation

Abstract

The advent of single cell transcriptome analysis has permitted the discovery of cell-to-cell variation in transcriptome expression of even presumptively identical cells. We hypothesize that this variability reflects a many-to-one relation between transcriptome states and the phenotype of a cell. In this relation, the molecular ratios of the subsets of RNA are determined by the stoichiometric constraints of the cell systems, which underdetermine the transcriptome state. Furthermore, the variability is, in part, induced by the tissue context and is important for system-level function. This theory is analogous to theories of literary deconstruction, where multiple 'signifiers' work in opposition to one another to create meaning. By analogy, transcriptome phenotypes should be defined as subsets of RNAs comprising selected RNA systems where the system-associated RNAs are balanced with each other to produce the associated cellular function. This idea provides a framework for understanding cellular heterogeneity in phenotypic responses to variant conditions, such as disease challenge.

Keywords: biological constraints; phenotype; transcriptome.

Figure 1

Individual cells of different mouse cell types clustered using cell type marker genes subset from whole single cell transcriptomes measured using in vitro transcription amplification and RNAseq. Reprinted with permission from [31].

Figure 2

A schematic diagram representing our conceptual model for the relationship between transcriptome and phenotype. Cells of a given external phenotype (e.g., neurons and fibroblasts; blue dots and green dots) are seen to map to broad domains of molecular state space (many-to-one relationship). The domains are determined by stoichiometric constraints of active pathways (schematically represented as inequalities). Some constraints may be nonlinear due to multi-component interactions (A>B²). Non-linear constraints may lead to population averages of cells being outside the state of any cell (red arrow). The constraints may change (e.g., from B>4 to B>6) due to physiological changes (e.g., aging) or external stimuli (e.g., chemotherapy drug) and the response of the cells may be heterogeneous due to original variation (red stars within blue dots representing neurons) explaining phenomena such as drug resistance or heterogeneous degeneration.

Figure 3

Comparison of Literary and Biological Deconstruction. The use of descriptors including words in literature and RNA for a cell represents an amalgam of other descriptors that through their opposing meanings or function elaborate the concepts of language and cellular phenotype.