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Abstract
Author SummaryDuring cell differentiation, progenitor cells respond to external signals that drive the expression of genes that are characteristic of the differentiated cell states. This process is controlled by gene regulatory networks that typically involve positive autoregulation and cross-inhibition between master regulators of the two differentiated states. Mapping the system's response to mixtures of external signals can help us to understand the operational logic of these binary cell fate decisions. Here, we study differentiation of CD4+ T cells into Th1 and Th2 lineages under mixed-input conditions, at the single cell level. We reveal that cell state is not restricted to a small number of well-defined phenotypes, but rather tunes through a continuum of mixed-phenotype states in which levels of lineage-specifying transcription factors gradually change with the levels of the two inputs. Using mathematical modeling we establish the conditions under which the system has one stable steady state that continuously tunes in response to changes in levels of the inputs. Results of this model qualitatively explain our experimental observations. We further characterize expression patterns of downstream lineage-specific genes—cytokines that are driven by the two master regulators upon cell re-stimulation. We find a highly heterogeneous population with cells expressing either one of the cytokines, both cytokines, or neither. Of note, the fraction of cells in these subpopulations continuously tunes with input levels, thus reproducing a tunable state at the cell population level. Our results can be explained by a two-stage scheme in which the gene regulatory network is responsible for a continuously tunable cell state, which is translated into a heterogeneous cytokine expression pattern through uncorrelated and biased stochastic processes.
Highlights
Consider a general cell differentiation process in which precursor cells can respond to two external signals, each driving differentiation into a specific lineage (Figure 1A)
Progenitor cells respond to external signals that drive the expression of genes that are characteristic of the differentiated cell states
We reveal that cell state is not restricted to a small number of welldefined phenotypes, but rather tunes through a continuum of mixed-phenotype states in which levels of lineagespecifying transcription factors gradually change with the levels of the two inputs
Summary
Consider a general cell differentiation process in which precursor cells can respond to two external signals, each driving differentiation into a specific lineage (Figure 1A). Most experimental and theoretical studies of cell differentiation show occurrence of such mutually exclusive steady states [4,5,6] Another scenario shown by other models is that of multistability (Figure 1C), where some input conditions give rise to a third steady state in which genes specific to both lineages are co-expressed. Tri-stability was observed in a number of systems in which low-level co-expression of lineage-specific transcription factors occurs in progenitor cells [7,8,9]. In both scenarios the transition between states is sharp. Cells can show a mixed phenotype at the single cell level, with individual
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