Abstract
There are an increasing number of reports that characterize the temporal behavior of gene expression at the single-cell level during cell differentiation. Despite accumulation of data describing the heterogeneity of biological responses, the dynamics of gene expression heterogeneity and its regulation during the differentiation process have not been studied systematically. To understand transcriptional heterogeneity during astrocyte differentiation, we analyzed single-cell transcriptional data from cells representing the different stages of astrocyte differentiation. When we compared the transcriptional variability of co-expressed genes between the undifferentiated and differentiated states, we found that there was significant increase in transcriptional variability in the undifferentiated state. The genes showing large changes in both “variability” and “correlation” between neural stem cells (NSCs) and astrocytes were found to be functionally involved in astrocyte differentiation. We determined that these genes are potentially regulated by Ascl1, a previously known oscillatory gene in NSCs. Pharmacological blockade of Ntsr2, which is transcriptionally co-regulated with Ascl1, showed that Ntsr2 may play an important role in the differentiation from NSCs to astrocytes. This study shows the importance of characterizing transcriptional heterogeneity and rearrangement of the co-regulation network between different cell states. It also highlights the potential for identifying novel regulators of cell differentiation that will further increase our understanding of the molecular mechanisms underlying the differentiation process.
Highlights
The variability in gene expression among individual cells is known to increase the complexity of cellular phenotypes due to the population effect.[1,2,3,4,5,6] Such an effect of cellular heterogeneity has been observed in various complex biological processes including disease progression, drug responses, and cell differentiation
By comparing TAPs/astrocytes vs. neuronal stem cells (NSCs), we evaluated the differences in gene expression variability using the single-cell gene expression data (Fig. 1a)
Between NSCs and astrocytes, 13.5% of all genes showed differential variability (Levene test q < 0.001). These data show that 1637 genes changed their expression profile, either in a harmonized or in a heterogeneous between cell states, we carried out our DVC analysis to identify candidate genes that could be predictive of an upcoming drastic cell state transition
Summary
The variability in gene expression among individual cells is known to increase the complexity of cellular phenotypes due to the population effect.[1,2,3,4,5,6] Such an effect of cellular heterogeneity has been observed in various complex biological processes including disease progression, drug responses, and cell differentiation. To understand the complexity of biological processes, it is important to investigate the mechanism of variability in gene expression and the co-expression relationships. Transcriptional variability is caused by factors that were greatly affected by the complexity of the cell population, such as individual differences in the cell state, the cell cycle, and in their biological profiles. In neuronal stem cells (NSCs), oscillations in gene expression are less synchronized, gene expression levels among individual cells show a large degree of diversity, resulting in a high degree of variability in gene expression in the cell population
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